Publications by authors named "Børge G Nordestgaard"

694 Publications

Plasma Concentrations of Magnesium and Risk of Dementia: A General Population Study of 102 648 Individuals.

Clin Chem 2021 Apr 13. Epub 2021 Apr 13.

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.

Background: Low and high concentrations of plasma magnesium are associated with increased risk of future all-cause dementia; however, the underlying reasons remain elusive. The magnesium ion is an important electrolyte serving as a cofactor in many enzymatic processes in the human organism. Magnesium affects both neuronal and vascular functions. We investigated the associations of plasma concentrations of magnesium associate with common subtypes of dementia as Alzheimer dementia and non-Alzheimer dementia, and potential pathways by which magnesium may affect risk of dementia.

Methods: Plasma concentrations of magnesium were measured in 102 648 individuals from the Copenhagen General Population Study. Cox regression and natural effects mediation analyses evaluated associations with either Alzheimer dementia or non-Alzheimer dementia.

Results: Multifactorially adjusted hazard ratios for non-Alzheimer dementia were 1.50(95% confidence interval (CI):1.21-1.87) for the lowest and 1.34(1.07-1.69) for the highest vs the fourth quintile (reference) of plasma magnesium concentrations. Diabetes, cumulated smoking, stroke, and systolic blood pressure mediated 10.4%(3.1-22.8%), 6.8%(1.2-14.0%), 1.3%(0.1-3.6%), and 1.0%(0.2-2.6%), respectively, in the lowest quintile, whereas stroke mediated 3.2%(0.4-11.9%) in the highest quintile. No associations were observed for Alzheimer dementia.

Conclusions: Low and high plasma magnesium concentrations were associated with high risk of vascular-related non-Alzheimer dementia, with the lowest risk observed at a concentration of 2.07 mg/dL (0.85 mmol/L). No association was observed for Alzheimer dementia. Mediation analysis suggested that diabetes may be in the causal pathway between low plasma magnesium concentrations and high risk of non-Alzheimer dementia, while cumulated smoking, stroke, and systolic blood pressure played minor mediating roles.
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http://dx.doi.org/10.1093/clinchem/hvab041DOI Listing
April 2021

Per-Particle Triglyceride-Rich Lipoproteins Imply Higher Myocardial Infarction Risk Than Low-Density Lipoproteins: Copenhagen General Population Study.

Arterioscler Thromb Vasc Biol 2021 Apr 8:ATVBAHA120315639. Epub 2021 Apr 8.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. (M.O.J., S.V.-K., S.F.N., S.A., B.G.N.).

Objective: ApoB (Apolipoprotein B)-containing triglyceride-rich lipoproteins and LDL (low-density lipoproteins) are each causal for myocardial infarction and atherosclerotic cardiovascular disease; however, the relative importance is unknown. We tested the hypothesis that for the same number of nonfasting apoB-containing particles from smaller LDL through to larger triglyceride-rich lipoproteins, the risk of myocardial infarction is similar. Approach and Results: We included 29 039 individuals with no history of myocardial infarction nested within 109 751 individuals from the Copenhagen General Population Study. Particle number of apoB-containing lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy. During a mean follow-up of 10 years, 2309 individuals developed myocardial infarction. Multivariable-adjusted hazard ratios for myocardial infarction per 1×10 particles were higher with larger size and more triglyceride content of apoB-containing lipoproteins using ten different subfractions, ranging from 11 (95% CI, 5.6-22) for extra extra large VLDL (very-low-density lipoproteins) to 1.06 (1.05-1.07) for extra small VLDL to 1.02 (1.01-1.02) for IDL (intermediate-density lipoproteins), through to 1.01 (1.01-1.01) for small LDL. When combining the particle number of 6 VLDL subfractions and combining IDL and 3 LDL subfractions, hazard ratios for myocardial infarction per 1×10 particles were 3.5 (2.7-4.5) for VLDL and 1.3 (1.2-1.4) for IDL and LDL combined.

Conclusions: For the same number of apoB-containing particles (1×10 particles/L), the hazard ratio for myocardial infarction was 3.5-fold for VLDL and 1.3-fold for IDL and LDL combined. Biological implications include that VLDL particles are more atherogenic than LDL particles and clinically that VLDL and LDL should be measured separately.
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http://dx.doi.org/10.1161/ATVBAHA.120.315639DOI Listing
April 2021

Impact of high glucose levels and glucose lowering on risk of ischaemic stroke: a Mendelian randomisation study and meta-analysis.

Diabetologia 2021 Mar 25. Epub 2021 Mar 25.

The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Aims/hypothesis: It is unclear whether glucose per se has a causal impact on risk of stroke and whether glucose-lowering drugs reduce this risk. This is important for the choice of treatment for individuals at risk. We tested the hypotheses that high plasma glucose has a causal impact on increased risk of ischaemic stroke, and that glucose-lowering drugs reduce this risk.

Methods: Using a Mendelian randomisation design, we examined 118,838 individuals from two Copenhagen cohorts, the Copenhagen General Population Study and the Copenhagen City Heart Study, and 440,328 individuals from the MEGASTROKE study. Effects of eight glucose-lowering drugs on risk of stroke were summarised by meta-analyses.

Results: In genetic, causal analyses, a 1 mmol/l higher plasma glucose had a risk ratio of 1.48 (95% CI 1.04, 2.11) for ischaemic stroke in the Copenhagen studies. The corresponding risk ratio from the MEGASTROKE study combined with the Copenhagen studies was 1.74 (1.31, 2.18). In meta-analyses of glucose-lowering drugs, the risk ratio for stroke was 0.85 (0.77, 0.94) for glucagon-like peptide-1 receptor agonists and 0.82 (0.69, 0.98) for thiazolidinediones, while sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, meglitinides and metformin individually lacked statistical evidence of an effect on stroke risk.

Conclusions/interpretation: Genetically high plasma glucose has a causal impact on increased risk of ischaemic stroke. Treatment with glucose-lowering glucagon-like peptide-1 receptor agonists and thiazolidinediones reduces this risk. These results may guide clinicians in the treatment of individuals at high risk of ischaemic stroke.
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http://dx.doi.org/10.1007/s00125-021-05436-0DOI Listing
March 2021

Genetic predisposition to long telomeres is associated with increased mortality after melanoma: a study of 2101 melanoma patients from hospital clinics and the general population.

Pigment Cell Melanoma Res 2021 Mar 22. Epub 2021 Mar 22.

Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.

Whether there is an association between measured and genetically predicted telomere length and melanoma mortality is unclear. We tested the hypotheses that measured and genetically predicted telomere length are associated with mortality after a melanoma diagnosis. We followed 2101patients with melanoma from hospital clinics and the general population for risk of death for up to 26 years. All had telomere length measured in DNA from leukocytes and 2052 of these were genotyped for the three single nucleotide polymorphisms rs7726159 (TERT), rs1317082 (TERC) and rs2487999 (OBFC1);all three genotypes are associated with telomere length, and combined into an allele count from 0 to 6. For each telomere-lengthening allele, the hazard ratios (HR) for mortality in the age-adjusted and multivariable adjusted Cox analysis were 1.12 (95% confidence interval: 1.02 - 1.23) and 1.11 (1.01 - 1.23).However, for each standard deviation increase in measured telomere length, HR for mortality was 0.97 (0.88 - 1.08). In conclusion, in more than 2000 melanoma patients from hospital clinics and from the general population, genetically predicted long telomeres were associated with increased mortality, but measured leukocyte telomere length was not.
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http://dx.doi.org/10.1111/pcmr.12971DOI Listing
March 2021

Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study.

Eur Heart J 2021 Mar;42(12):1147-1156

Department of Clinical Biochemistry, Borgmester Ib Juuls Vej 73, opgang 7, Herlev 2730, Denmark.

Aims: With the current focus on lipoprotein(a) as a likely causal risk factor for cardiovascular disease and new drugs potentially on the market to lower lipoprotein(a) levels, the safety of lowering lipoprotein(a) to low levels becomes increasingly important. We tested whether low levels of lipoprotein(a) and corresponding LPA genotypes associate with major disease groups including cancers and infectious disease.

Methods And Results: We included 109 440 individuals from the Copenhagen General Population Study. For main World Health Organization International Classification of Diseases 10th edition chapter diseases, the only concordant association of low levels of lipoprotein(a) plasma levels and corresponding LPA genotypes with risk of disease was with low risk of diseases of the circulatory system. Furthermore, no concordant association of low levels of lipoprotein(a) plasma levels and corresponding LPA genotypes with the risk of any cancer (i.e. cancer subtypes combined) or infectious disease was seen. The hazard ratio for the risk of any cancer was 1.06 [95% confidence interval (CI): 0.97-1.15] for the first vs. the fourth quartile of lipoprotein(a), 1.02 (0.97-1.07) for the fourth vs. the first quartile of KIV-2 number of repeats, and 1.01 (0.96-1.07) for rs10455872 non-carriers vs. carriers. The corresponding hazard ratios for the risk of hospitalization for infection were 1.05 (95% CI: 0.99-1.10), 1.02 (0.98-1.07), and 0.97 (0.93-1.03), respectively.

Conclusion: In a large, contemporary, general population cohort, apart from the well-established association with cardiovascular disease, low levels of lipoprotein(a) and corresponding LPA genotypes did not concordantly associate with any major disease groups including cancers and infections. There is no safety signal from our results to indicate that low levels of lipoprotein(a) are harmful.
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http://dx.doi.org/10.1093/eurheartj/ehaa1085DOI Listing
March 2021

Identification of two different coagulation phenotypes in people living with HIV with undetectable viral replication.

Sci Rep 2021 Feb 23;11(1):4383. Epub 2021 Feb 23.

Viro-Immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Blegdamsvej 9B, 2100, Copenhagen Ø, Denmark.

Altered coagulation has been reported in people living with HIV (PLWH) with ongoing viral replication and may predispose to cardiovascular diseases. However, less is known about coagulation in PLWH with undetectable viral replication. In a cross-sectional observational study, we investigated whether HIV infection with undetectable viral replication is independently associated with activated partial thromboplastin time (APTT) and coagulation factor II-VII-X concentrations out of reference. Logistic regression analyses were used to assess the association of HIV infection with APTT and coagulation factor II-VII-X, after adjusting for age, sex, smoking status, alcohol consumption, BMI, diabetes and hsCRP. 936 PLWH with undetectable viral replication from the Copenhagen Co-morbidity in HIV infection study (COCOMO-study) and 2955 uninfected controls were included. Higher prevalence of short APTT was found in PLWH compared to controls (13.5% vs. 7.6%, P < 0.001). Furthermore, higher prevalence of low coagulation factor II-VII-X was found in PLWH than in controls (9.6% vs. 7.4%, P = 0.022). HIV was independently associated with short APTT (adjusted odds ratio (aOR) 2.3 (95% CI 1.7-2.9), P < 0.001) and low coagulation factor II-VII-X (aOR 1.4 (95% CI 1.0-1.9), P = 0.046). Few participants among PLWH and controls had both short APTT and low coagulation factor II-VII-X, 2.1% vs. 0.8%, respectively. We found evidence of both procoagulant (short APTT) and anticoagulant (low coagulation factor II-VII-X) alterations in PLWH with undetectable viral replication, and our findings suggest that two different coagulation phenotypes exist in participants with treated HIV infection.
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http://dx.doi.org/10.1038/s41598-021-83731-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902813PMC
February 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Chronic productive cough and inhalant occupational exposure-a study of the general population.

Int Arch Occup Environ Health 2021 Feb 9. Epub 2021 Feb 9.

Department of Occupational and Environmental Medicine, Bispebjerg Frederiksberg Hospital, Copenhagen University Hospital, Bispebjerg Bakke 23, 2400, Copenhagen, NV, Denmark.

Purpose: Occupational inhalant exposures have been linked with a higher occurrence of chronic productive cough, but recent studies question the association.

Methods: We included participants from two general population studies, the Copenhagen City General Population Study and the Copenhagen City Heart Study, to assess contemporary (year 2003-2017) and historical (1976-1983) occupational inhalant hazards. Job titles one year prior to study inclusion and an airborne chemical job-exposure matrix (ACE JEM) were used to estimate occupational exposure. The association between occupational exposures and self-reported chronic productive cough was studied using generalized estimating equations stratified by smoking status and cohort.

Results: The population consisted of 5210 working individuals aged 20-65 from 1976 to 1983 and 64,279 from 2003 to 2017. In smokers, exposure to high levels of mineral dust, biological dust, gases & fumes and the composite variable vapours, gases, dusts or fumes (VGDF) were associated with chronic productive cough in both cohorts with odds ratios in the range of 1.2 (95% confidence interval, 1.0;1.4) to 1.6 (1.2;2.1). High levels of biological dust were only associated with an increased risk of a chronic productive cough in the 2003-2017 cohort (OR 1.5 (1.1;2.0)). In non-smokers, high levels of VGDF (OR 1.5 (1.0;2.3)) and low levels of mineral dust (OR 1.7 (1.1;2.4)) were associated with chronic productive cough in the 1976-1983 cohort, while no associations were seen in non-smokers in the 2003-2017 cohort.

Conclusion: Occupational inhalant exposure remains associated with a modestly increased risk of a chronic productive cough in smokers, despite declining exposure levels during the past four decades.
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http://dx.doi.org/10.1007/s00420-020-01634-2DOI Listing
February 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Authors:
Anna Morra Audrey Y Jung Sabine Behrens Renske Keeman Thomas U Ahearn Hoda Anton-Culver Volker Arndt Annelie Augustinsson Päivi K Auvinen Laura E Beane Freeman Heiko Becher Matthias W Beckmann Carl Blomqvist Stig E Bojesen Manjeet K Bolla Hermann Brenner Ignacio Briceno Sara Y Brucker Nicola J Camp Daniele Campa Federico Canzian Jose E Castelao Stephen J Chanock Ji-Yeob Choi Christine L Clarke Fergus J Couch Angela Cox Simon S Cross Kamila Czene Thilo Dörk Alison M Dunning Miriam Dwek Douglas F Easton Diana M Eccles Kathleen M Egan D Gareth Evans Peter A Fasching Henrik Flyger Manuela Gago-Dominguez Susan M Gapstur José A García-Sáenz Mia M Gaudet Graham G Giles Mervi Grip Pascal Guénel Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Sileny N Han Steven N Hart Mikael Hartman Jane S Heyworth Reiner Hoppe John L Hopper David J Hunter Hidemi Ito Agnes Jager Milena Jakimovska Anna Jakubowska Wolfgang Janni Rudolf Kaaks Daehee Kang Pooja Middha Kapoor Cari M Kitahara Stella Koutros Peter Kraft Vessela N Kristensen James V Lacey Diether Lambrechts Loic Le Marchand Jingmei Li Annika Lindblom Jan Lubiński Michael Lush Arto Mannermaa Mehdi Manoochehri Sara Margolin Shivaani Mariapun Keitaro Matsuo Dimitrios Mavroudis Roger L Milne Taru A Muranen William G Newman Dong-Young Noh Børge G Nordestgaard Nadia Obi Andrew F Olshan Håkan Olsson Tjoung-Won Park-Simon Christos Petridis Paul D P Pharoah Dijana Plaseska-Karanfilska Nadege Presneau Muhammad U Rashid Gad Rennert Hedy S Rennert Valerie Rhenius Atocha Romero Emmanouil Saloustros Elinor J Sawyer Andreas Schneeweiss Lukas Schwentner Christopher Scott Mitul Shah Chen-Yang Shen Xiao-Ou Shu Melissa C Southey Daniel O Stram Rulla M Tamimi William Tapper Rob A E M Tollenaar Ian Tomlinson Diana Torres Melissa A Troester Thérèse Truong Celine M Vachon Qin Wang Sophia S Wang Justin A Williams Robert Winqvist Alicja Wolk Anna H Wu Keun-Young Yoo Jyh-Cherng Yu Wei Zheng Argyrios Ziogas Xiaohong R Yang A Heather Eliassen Michelle D Holmes Montserrat García-Closas Soo Hwang Teo Marjanka K Schmidt Jenny Chang-Claude

Cancer Epidemiol Biomarkers Prev 2021 Apr 26;30(4):623-642. Epub 2021 Jan 26.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Authors:
Nichola Johnson Sarah Maguire Anna Morra Pooja Middha Kapoor Katarzyna Tomczyk Michael E Jones Minouk J Schoemaker Clare Gilham Manjeet K Bolla Qin Wang Joe Dennis Thomas U Ahearn Irene L Andrulis Hoda Anton-Culver Natalia N Antonenkova Volker Arndt Kristan J Aronson Annelie Augustinsson Caroline Baynes Laura E Beane Freeman Matthias W Beckmann Javier Benitez Marina Bermisheva Carl Blomqvist Bram Boeckx Natalia V Bogdanova Stig E Bojesen Hiltrud Brauch Hermann Brenner Barbara Burwinkel Daniele Campa Federico Canzian Jose E Castelao Stephen J Chanock Georgia Chenevix-Trench Christine L Clarke Don M Conroy Fergus J Couch Angela Cox Simon S Cross Kamila Czene Thilo Dörk A Heather Eliassen Christoph Engel D Gareth Evans Peter A Fasching Jonine Figueroa Giuseppe Floris Henrik Flyger Manuela Gago-Dominguez Susan M Gapstur Montserrat García-Closas Mia M Gaudet Graham G Giles Mark S Goldberg Anna González-Neira Pascal Guénel Eric Hahnen Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Steven N Hart Maartje J Hooning John L Hopper Anthony Howell David J Hunter Agnes Jager Anna Jakubowska Esther M John Rudolf Kaaks Renske Keeman Elza Khusnutdinova Cari M Kitahara Veli-Matti Kosma Stella Koutros Peter Kraft Vessela N Kristensen Allison W Kurian Diether Lambrechts Loic Le Marchand Martha Linet Jan Lubiński Arto Mannermaa Siranoush Manoukian Sara Margolin John W M Martens Dimitrios Mavroudis Rebecca Mayes Alfons Meindl Roger L Milne Susan L Neuhausen Heli Nevanlinna William G Newman Sune F Nielsen Børge G Nordestgaard Nadia Obi Andrew F Olshan Janet E Olson Håkan Olsson Ester Orban Tjoung-Won Park-Simon Paolo Peterlongo Dijana Plaseska-Karanfilska Katri Pylkäs Gad Rennert Hedy S Rennert Kathryn J Ruddy Emmanouil Saloustros Dale P Sandler Elinor J Sawyer Rita K Schmutzler Christopher Scott Xiao-Ou Shu Jacques Simard Snezhana Smichkoska Christof Sohn Melissa C Southey John J Spinelli Jennifer Stone Rulla M Tamimi Jack A Taylor Rob A E M Tollenaar Ian Tomlinson Melissa A Troester Thérèse Truong Celine M Vachon Elke M van Veen Sophia S Wang Clarice R Weinberg Camilla Wendt Hans Wildiers Robert Winqvist Alicja Wolk Wei Zheng Argyrios Ziogas Alison M Dunning Paul D P Pharoah Douglas F Easton A Forbes Howie Julian Peto Isabel Dos-Santos-Silva Anthony J Swerdlow Jenny Chang-Claude Marjanka K Schmidt Nick Orr Olivia Fletcher

Br J Cancer 2021 Feb 26;124(4):842-854. Epub 2021 Jan 26.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Authors:
David V Conti Burcu F Darst Lilit C Moss Edward J Saunders Xin Sheng Alisha Chou Fredrick R Schumacher Ali Amin Al Olama Sara Benlloch Tokhir Dadaev Mark N Brook Ali Sahimi Thomas J Hoffmann Atushi Takahashi Koichi Matsuda Yukihide Momozawa Masashi Fujita Kenneth Muir Artitaya Lophatananon Peggy Wan Loic Le Marchand Lynne R Wilkens Victoria L Stevens Susan M Gapstur Brian D Carter Johanna Schleutker Teuvo L J Tammela Csilla Sipeky Anssi Auvinen Graham G Giles Melissa C Southey Robert J MacInnis Cezary Cybulski Dominika Wokołorczyk Jan Lubiński David E Neal Jenny L Donovan Freddie C Hamdy Richard M Martin Børge G Nordestgaard Sune F Nielsen Maren Weischer Stig E Bojesen Martin Andreas Røder Peter Iversen Jyotsna Batra Suzanne Chambers Leire Moya Lisa Horvath Judith A Clements Wayne Tilley Gail P Risbridger Henrik Gronberg Markus Aly Robert Szulkin Martin Eklund Tobias Nordström Nora Pashayan Alison M Dunning Maya Ghoussaini Ruth C Travis Tim J Key Elio Riboli Jong Y Park Thomas A Sellers Hui-Yi Lin Demetrius Albanes Stephanie J Weinstein Lorelei A Mucci Edward Giovannucci Sara Lindstrom Peter Kraft David J Hunter Kathryn L Penney Constance Turman Catherine M Tangen Phyllis J Goodman Ian M Thompson Robert J Hamilton Neil E Fleshner Antonio Finelli Marie-Élise Parent Janet L Stanford Elaine A Ostrander Milan S Geybels Stella Koutros Laura E Beane Freeman Meir Stampfer Alicja Wolk Niclas Håkansson Gerald L Andriole Robert N Hoover Mitchell J Machiela Karina Dalsgaard Sørensen Michael Borre William J Blot Wei Zheng Edward D Yeboah James E Mensah Yong-Jie Lu Hong-Wei Zhang Ninghan Feng Xueying Mao Yudong Wu Shan-Chao Zhao Zan Sun Stephen N Thibodeau Shannon K McDonnell Daniel J Schaid Catharine M L West Neil Burnet Gill Barnett Christiane Maier Thomas Schnoeller Manuel Luedeke Adam S Kibel Bettina F Drake Olivier Cussenot Géraldine Cancel-Tassin Florence Menegaux Thérèse Truong Yves Akoli Koudou Esther M John Eli Marie Grindedal Lovise Maehle Kay-Tee Khaw Sue A Ingles Mariana C Stern Ana Vega Antonio Gómez-Caamaño Laura Fachal Barry S Rosenstein Sarah L Kerns Harry Ostrer Manuel R Teixeira Paula Paulo Andreia Brandão Stephen Watya Alexander Lubwama Jeannette T Bensen Elizabeth T H Fontham James Mohler Jack A Taylor Manolis Kogevinas Javier Llorca Gemma Castaño-Vinyals Lisa Cannon-Albright Craig C Teerlink Chad D Huff Sara S Strom Luc Multigner Pascal Blanchet Laurent Brureau Radka Kaneva Chavdar Slavov Vanio Mitev Robin J Leach Brandi Weaver Hermann Brenner Katarina Cuk Bernd Holleczek Kai-Uwe Saum Eric A Klein Ann W Hsing Rick A Kittles Adam B Murphy Christopher J Logothetis Jeri Kim Susan L Neuhausen Linda Steele Yuan Chun Ding William B Isaacs Barbara Nemesure Anselm J M Hennis John Carpten Hardev Pandha Agnieszka Michael Kim De Ruyck Gert De Meerleer Piet Ost Jianfeng Xu Azad Razack Jasmine Lim Soo-Hwang Teo Lisa F Newcomb Daniel W Lin Jay H Fowke Christine Neslund-Dudas Benjamin A Rybicki Marija Gamulin Davor Lessel Tomislav Kulis Nawaid Usmani Sandeep Singhal Matthew Parliament Frank Claessens Steven Joniau Thomas Van den Broeck Manuela Gago-Dominguez Jose Esteban Castelao Maria Elena Martinez Samantha Larkin Paul A Townsend Claire Aukim-Hastie William S Bush Melinda C Aldrich Dana C Crawford Shiv Srivastava Jennifer C Cullen Gyorgy Petrovics Graham Casey Monique J Roobol Guido Jenster Ron H N van Schaik Jennifer J Hu Maureen Sanderson Rohit Varma Roberta McKean-Cowdin Mina Torres Nicholas Mancuso Sonja I Berndt Stephen K Van Den Eeden Douglas F Easton Stephen J Chanock Michael B Cook Fredrik Wiklund Hidewaki Nakagawa John S Witte Rosalind A Eeles Zsofia Kote-Jarai Christopher A Haiman

Nat Genet 2021 Mar;53(3):413

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1038/s41588-021-00786-2DOI Listing
March 2021

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Authors:
Leila Dorling Sara Carvalho Jamie Allen Anna González-Neira Craig Luccarini Cecilia Wahlström Karen A Pooley Michael T Parsons Cristina Fortuno Qin Wang Manjeet K Bolla Joe Dennis Renske Keeman M Rosario Alonso Nuria Álvarez Belen Herraez Victoria Fernandez Rocio Núñez-Torres Ana Osorio Jeanette Valcich Minerva Li Therese Törngren Patricia A Harrington Caroline Baynes Don M Conroy Brennan Decker Laura Fachal Nasim Mavaddat Thomas Ahearn Kristiina Aittomäki Natalia N Antonenkova Norbert Arnold Patrick Arveux Margreet G E M Ausems Päivi Auvinen Heiko Becher Matthias W Beckmann Sabine Behrens Marina Bermisheva Katarzyna Białkowska Carl Blomqvist Natalia V Bogdanova Nadja Bogdanova-Markov Stig E Bojesen Bernardo Bonanni Anne-Lise Børresen-Dale Hiltrud Brauch Michael Bremer Ignacio Briceno Thomas Brüning Barbara Burwinkel David A Cameron Nicola J Camp Archie Campbell Angel Carracedo Jose E Castelao Melissa H Cessna Stephen J Chanock Hans Christiansen J Margriet Collée Emilie Cordina-Duverger Sten Cornelissen Kamila Czene Thilo Dörk Arif B Ekici Christoph Engel Mikael Eriksson Peter A Fasching Jonine Figueroa Henrik Flyger Asta Försti Marike Gabrielson Manuela Gago-Dominguez Vassilios Georgoulias Fabian Gil Graham G Giles Gord Glendon Encarna B Gómez Garcia Grethe I Grenaker Alnæs Pascal Guénel Andreas Hadjisavvas Lothar Haeberle Eric Hahnen Per Hall Ute Hamann Elaine F Harkness Jaana M Hartikainen Mikael Hartman Wei He Bernadette A M Heemskerk-Gerritsen Peter Hillemanns Frans B L Hogervorst Antoinette Hollestelle Weang Kee Ho Maartje J Hooning Anthony Howell Keith Humphreys Faiza Idris Anna Jakubowska Audrey Jung Pooja Middha Kapoor Michael J Kerin Elza Khusnutdinova Sung-Won Kim Yon-Dschun Ko Veli-Matti Kosma Vessela N Kristensen Kyriacos Kyriacou Inge M M Lakeman Jong Won Lee Min Hyuk Lee Jingmei Li Annika Lindblom Wing-Yee Lo Maria A Loizidou Artitaya Lophatananon Jan Lubiński Robert J MacInnis Michael J Madsen Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin Maria Elena Martinez Tabea Maurer Dimitrios Mavroudis Catriona McLean Alfons Meindl Arjen R Mensenkamp Kyriaki Michailidou Nicola Miller Nur Aishah Mohd Taib Kenneth Muir Anna Marie Mulligan Heli Nevanlinna William G Newman Børge G Nordestgaard Pei-Sze Ng Jan C Oosterwijk Sue K Park Tjoung-Won Park-Simon Jose I A Perez Paolo Peterlongo David J Porteous Karolina Prajzendanc Darya Prokofyeva Paolo Radice Muhammad U Rashid Valerie Rhenius Matti A Rookus Thomas Rüdiger Emmanouil Saloustros Elinor J Sawyer Rita K Schmutzler Andreas Schneeweiss Peter Schürmann Mitul Shah Christof Sohn Melissa C Southey Harald Surowy Maija Suvanto Somchai Thanasitthichai Ian Tomlinson Diana Torres Thérèse Truong Maria Tzardi Yana Valova Christi J van Asperen Rob M Van Dam Ans M W van den Ouweland Lizet E van der Kolk Elke M van Veen Camilla Wendt Justin A Williams Xiaohong R Yang Sook-Yee Yoon M Pilar Zamora D Gareth Evans Miguel de la Hoya Jacques Simard Antonis C Antoniou Åke Borg Irene L Andrulis Jenny Chang-Claude Montserrat García-Closas Georgia Chenevix-Trench Roger L Milne Paul D P Pharoah Marjanka K Schmidt Amanda B Spurdle Maaike P G Vreeswijk Javier Benitez Alison M Dunning Anders Kvist Soo H Teo Peter Devilee Douglas F Easton

N Engl J Med 2021 02 20;384(5):428-439. Epub 2021 Jan 20.

The authors' affiliations are as follows: the Centre for Cancer Genetic Epidemiology, Departments of Public Health and Primary Care (L.D., S. Carvalho, J.A., K.A.P., Q.W., M.K.B., J.D., B.D., N. Mavaddat, K. Michailidou, A.C.A., P.D.P.P., D.F.E.) and Oncology (C.L., P.A.H., C. Baynes, D.M.C., L.F., V.R., M. Shah, P.D.P.P., A.M.D., D.F.E.), University of Cambridge, Cambridge, the Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine (A. Campbell, D.J.P.), and the Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology (D.J.P.), University of Edinburgh, the Cancer Research UK Edinburgh Centre (D.A.C., J.F.), and the Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School (A. Campbell, J.F.), Edinburgh, the Divisions of Informatics, Imaging, and Data Sciences (E.F.H.), Cancer Sciences (A. Howell), Population Health, Health Services Research, and Primary Care (A. Lophatananon, K. Muir), and Evolution and Genomic Sciences, School of Biological Sciences (W.G.N., E.M.V., D.G.E.), University of Manchester, the NIHR Manchester Biomedical Research Unit (E.F.H.) and the Nightingale Breast Screening Centre, Wythenshawe Hospital (E.F.H., H.I.), Academic Health Science Centre and North West Genomics Laboratory Hub, and the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust (W.G.N., E.M.V., D.G.E.), Manchester, the School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London (E.J.S.), the Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham (I.T.), and the Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford (I.T.) - all in the United Kingdom; the Human Genotyping-CEGEN Unit, Human Cancer Genetic Program (A.G.-N., M.R.A., N.Á., B.H., R.N.-T.), and the Human Genetics Group (V.F., A.O., J.B.), Spanish National Cancer Research Center, Centro de Investigación en Red de Enfermedades Raras (A.O., J.B.), Servicio de Oncología Médica, Hospital Universitario La Paz (M.P.Z.), and Molecular Oncology Laboratory, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (M. de la Hoya), Madrid, the Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago (A. Carracedo, M.G.-D.), and Centro de Investigación en Red de Enfermedades Raras y Centro Nacional de Genotipado, Universidad de Santiago de Compostela (A. Carracedo), Santiago de Compostela, the Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur, Xerencia de Xestion Integrada de Vigo-Servizo Galeo de Saúde, Vigo (J.E.C.), and Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo (J.I.A.P.) - all in Spain; the Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund (C. Wahlström, J.V., M.L., T. Törngren, Å.B., A.K.), the Department of Oncology, Örebro University Hospital, Örebro (C. Blomqvist), and the Departments of Medical Epidemiology and Biostatistics (K.C., M.E., M.G., P. Hall, W.H., K.H.), Oncology, Södersjukhuset (P. Hall, S. Margolin), Molecular Medicine and Surgery (A. Lindblom), and Clinical Science and Education, Södersjukhuset (S. Margolin, C. Wendt), Karolinska Institutet, and the Department of Clinical Genetics, Karolinska University Hospital (A. Lindblom), Stockholm - all in Sweden; the Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD (M.T.P., C.F., G.C.-T., A.B.S.), the Cancer Epidemiology Division, Cancer Council Victoria (G.G.G., R.J.M., R.L.M.), the Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health (G.G.G., R.J.M., R.L.M.), and the Department of Clinical Pathology (M.C.S.), University of Melbourne, Anatomical Pathology, Alfred Hospital (C.M.), and the Cancer Epidemiology Division, Cancer Council Victoria (M.C.S.), Melbourne, VIC, and Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC (G.G.G., M.C.S., R.L.M.) - all in Australia; the Division of Molecular Pathology (R.K., S. Cornelissen, M.K.S.), Family Cancer Clinic (F.B.L.H., L.E.K.), Department of Epidemiology (M.A.R.), and Division of Psychosocial Research and Epidemiology (M.K.S.), the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center, Utrecht (M.G.E.M.A.), the Department of Clinical Genetics, Erasmus University Medical Center (J.M.C., A.M.W.O.), and the Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute (B.A.M.H.-G., A. Hollestelle, M.J.H.), Rotterdam, the Department of Clinical Genetics, Maastricht University Medical Center, Maastricht (E.B.G.G.), the Departments of Human Genetics (I.M.M.L., M.P.G.V., P.D.), Clinical Genetics (C.J.A.), and Pathology (P.D.), Leiden University Medical Center, Leiden, the Department of Human Genetics, Radboud University Medical Center, Nijmegen (A.R.M.), and the Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen (J.C.O.) - all in the Netherlands; the Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute (B.D.), and the Division of Cancer Epidemiology and Genetics, National Cancer Institute (T.A., S.J.C., X.R.Y., M.G.-C.), National Institutes of Health, Bethesda, MD; the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School (B.D.), and the Department of Nutrition, Harvard T.H. Chan School of Public Health (R.M.V.D.), Boston; the Departments of Clinical Genetics (K.A.), Oncology (C. Blomqvist), and Obstetrics and Gynecology (H.N., M. Suvanto), Helsinki University Hospital, University of Helsinki, Helsinki, and the Unit of Clinical Oncology, Kuopio University Hospital (P. Auvinen), the Institute of Clinical Medicine, Oncology (P. Auvinen), the Translational Cancer Research Area (J.M.H., V.-M.K., A. Mannermaa), and the Institute of Clinical Medicine, Pathology, and Forensic Medicine (J.M.H., V.-M.K., A. Mannermaa), University of Eastern Finland, and the Biobank of Eastern Finland, Kuopio University Hospital (V.-M.K., A. Mannermaa), Kuopio - both in Finland; the N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus (N.N.A., N.V.B.); the Department of Gynecology and Obstetrics and Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel (N.A.), the Institute of Medical Biometry and Epidemiology (H. Becher) and Cancer Epidemiology Group (T.M., J.C.-C.), University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, the Department of Gynecology and Obstetrics (M.W.B., P.A.F., L.H.) and Institute of Human Genetics (A.B.E.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Erlangen, the Division of Cancer Epidemiology (S.B., A. Jung, P.M.K., J.C.-C.), Molecular Epidemiology Group, C080 (B. Burwinkel, H.S.), Division of Pediatric Neurooncology (A.F.), and Molecular Genetics of Breast Cancer (U.H., M.M., M.U.R., D.T.), German Cancer Research Center, Molecular Biology of Breast Cancer, University Women's Clinic Heidelberg, University of Heidelberg (B. Burwinkel, A.S., H.S.), Hopp Children's Cancer Center (A.F.), Faculty of Medicine, University of Heidelberg (P.M.K.), and National Center for Tumor Diseases, University Hospital and German Cancer Research Center (A.S., C.S.), Heidelberg, the Department of Radiation Oncology (N.V.B., M. Bremer, H.C.) and the Gynecology Research Unit (N.V.B., T.D., P. Hillemanns, T.-W.P.-S., P.S.), Hannover Medical School, Hannover, the Institute of Human Genetics, University of Münster, Münster (N.B.-M.), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart (H. Brauch, W.-Y.L.), iFIT-Cluster of Excellence, University of Tübingen, and the German Cancer Consortium, German Cancer Research Center, Partner Site Tübingen (H. Brauch), and the University of Tübingen (W.-Y.L.), Tübingen, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum (T.B.), Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig (C.E.), Center for Hereditary Breast and Ovarian Cancer (E.H., R.K.S.) and Center for Integrated Oncology (E.H., R.K.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, the Department of Internal Medicine, Evangelische Kliniken Bonn, Johanniter Krankenhaus, Bonn (Y.-D.K.), the Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich (A. Meindl), and the Institute of Pathology, Städtisches Klinikum Karlsruhe, Karlsruhe (T.R.) - all in Germany; the Gynecological Cancer Registry, Centre Georges-François Leclerc, Dijon (P. Arveux), and the Center for Research in Epidemiology and Population Health, Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif (E.C.-D., P.G., T. Truong) - both in France; the Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences (M. Bermisheva, E.K.), the Department of Genetics and Fundamental Medicine, Bashkir State University (E.K., D.P., Y.V.), and the Ufa Research Institute of Occupational Health and Human Ecology (Y.V.), Ufa, Russia; the Department of Genetics and Pathology (K.B., A. Jakubowska, J. Lubiński, K.P.) and the Independent Laboratory of Molecular Biology and Genetic Diagnostics (A. Jakubowska), Pomeranian Medical University, Szczecin, Poland; the Copenhagen General Population Study, the Department of Clinical Biochemistry (S.E.B., B.G.N.), and the Department of Breast Surgery (H.F.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, and the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (S.E.B., B.G.N.) - both in Denmark; the Division of Cancer Prevention and Genetics, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) (B. Bonanni), the Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (S. Manoukian), the Genome Diagnostics Program, FIRC Institute of Molecular Oncology (P.P.), and the Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (P.R.), Milan; the Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet (A.-L.B.-D., G.I.G.A., V.N.K.), and the Institute of Clinical Medicine, Faculty of Medicine, University of Oslo (A.-L.B.-D., V.N.K.), Oslo; Medical Faculty, Universidad de La Sabana (I.B.), and the Clinical Epidemiology and Biostatistics Department (F.G.) and Institute of Human Genetics (D.T.), Pontificia Universidad Javeriana, Bogota, Colombia; the Department of Internal Medicine and Huntsman Cancer Institute, University of Utah (N.J.C., M.J.M., J.A.W.), and the Intermountain Healthcare Biorepository and Department of Pathology, Intermountain Healthcare (M.H.C.), Salt Lake City; the David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California, Los Angeles (P.A.F.), and Moores Cancer Center (M.G.-D., M.E.M.) and the Department of Family Medicine and Public Health (M.E.M.), University of California San Diego, La Jolla; the Departments of Medical Oncology (V.G., D.M.) and Pathology (M.T.), University Hospital of Heraklion, Heraklion, and the Department of Oncology, University Hospital of Larissa, Larissa (E.S.) - both in Greece; the Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital (G.G., I.L.A.), the Departments of Laboratory Medicine and Pathobiology (A.M.M.) and Molecular Genetics (I.L.A.), University of Toronto, and the Laboratory Medicine Program, University Health Network (A.M.M.), Toronto, and the Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC (J.S.) - both in Canada; the Department of Electron Microscopy and Molecular Pathology (A. Hadjisavvas, K.K., M.A.L.), the Cyprus School of Molecular Medicine (A. Hadjisavvas, K.K., M.A.L., K. Michailidou), and the Biostatistics Unit (K. Michailidou), Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; the Saw Swee Hock School of Public Health (M. Hartman, R.M.V.D.) and the Department of Medicine, Yong Loo Lin School of Medicine (R.M.V.D.), National University of Singapore, the Department of Surgery, National University Health System (M. Hartman, J. Li), and the Human Genetics Division, Genome Institute of Singapore (J. Li), Singapore; the Department of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia (W.K.H.), and the Breast Cancer Research Programme, Cancer Research Malaysia (W.K.H., P.S.N., S.-Y.Y., S.H.T.), Selangor, and the Breast Cancer Research Unit, Cancer Research Institute (N.A.M.T.), and the Department of Surgery, Faculty of Medicine (N.A.M.T., P.S.N., S.H.T.), University Malaya, Kuala Lumpur - both in Malaysia; Surgery, School of Medicine, National University of Ireland, Galway (M.J.K., N. Miller); the Department of Surgery, Daerim Saint Mary's Hospital (S.-W.K.), the Department of Surgery, Ulsan University College of Medicine and Asan Medical Center (J.W.L.), the Department of Surgery, Soonchunhyang University College of Medicine and Soonchunhyang University Hospital (M.H.L.), Integrated Major in Innovative Medical Science, Seoul National University College of Medicine (S.K.P.), and the Cancer Research Institute, Seoul National University (S.K.P.), Seoul, South Korea; the Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M.U.R.); and the National Cancer Institute, Ministry of Public Health, Nonthaburi, Thailand (S.T.).

Background: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

Methods: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

Results: Protein-truncating variants in 5 genes (, , , , and ) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (, , , and ) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in and , odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in , , , , , and , odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in , , and were associated with a risk of breast cancer overall with a P value of less than 0.001. For , , and , missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.

Conclusions: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).
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http://dx.doi.org/10.1056/NEJMoa1913948DOI Listing
February 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jan 8. Epub 2021 Jan 8.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
January 2021

Triglycerides as a Shared Risk Factor between Dementia and Atherosclerotic Cardiovascular Disease: A Study of 125 727 Individuals.

Clin Chem 2021 Jan;67(1):245-255

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Risk factors for atherosclerotic cardiovascular disease such as smoking, hypertension, physical inactivity, and diabetes have also been associated with risk of dementia. Whether hypertriglyceridemia represents a shared risk factor as well remains unknown. We tested the hypothesis that hypertriglyceridemia is associated with increased risk of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke.

Methods: Using the Copenhagen General Population Study and the Copenhagen City Heart Study, we examined the association between increased plasma triglycerides and risk of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke with Cox regression.

Results: On a continuous scale, higher concentrations of plasma triglycerides were associated with increased risk of non-Alzheimer dementia and ischemic stroke, but not with Alzheimer disease. In age, sex, and cohort adjusted models, the highest percentile of triglycerides (median 629 mg/dL; 7.1 mmol/L) versus the 1-50th percentiles (median 89 mg/dL; 1.0 mmol/L) was associated with hazard ratios of 1.75 (95% confidence interval: 1.17-2.63) for non-Alzheimer dementia, 1.18 (0.73-1.91) for Alzheimer disease, and of 1.89 (1.50-2.38) for ischemic stroke. Corresponding hazard ratios were 1.62 (1.08-2.44), 1.25 (0.77-2.02), and 1.57 (1.24-1.98) in models adjusted multifactorially, and 1.79 (1.16-2.87), 1.18 (0.73-1.92), and 1.46 (1.10-1.95) in models adjusted multifactorially and additionally for apolipoprotein E (APOE) genotype, respectively. Results were similar after excluding individuals who had an event within 2 years after study entry.

Conclusions: Moderate hypertriglyceridemia was associated with increased risk of both non-Alzheimer dementia and ischemic stroke, highlighting plasma triglycerides as a shared risk factor between dementia and atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1093/clinchem/hvaa269DOI Listing
January 2021

Plasma Ionized Calcium and Risk of Cardiovascular Disease: 106 774 Individuals from the Copenhagen General Population Study.

Clin Chem 2021 Jan;67(1):265-275

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Circulating total calcium or albumin-adjusted calcium is a risk factor for cardiovascular disease. As the biologically active ionized calcium is a physiologically more relevant measure and its association with cardiovascular disease is poorly understood, we tested the hypothesis that high plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke in individuals in the general population.

Methods: We included 106 774 individuals from the Copenhagen General Population Study, and defined hypocalcemia and hypercalcemia by the lowest and highest 2.5 percentiles, respectively, using the central 95% reference interval. Information on myocardial infarction and ischemic stroke was from registries and risks calculated using Cox regression and Fine and Gray competing-risks regression.

Results: During a median follow-up of 9.2 years, 4932 individuals received a diagnosis of either myocardial infarction or ischemic stroke. Hypercalcemia was associated with subdistribution hazard ratios of 1.67 (95%CI: 1.05-2.67) for myocardial infarction, 1.28 (0.81-2.02) for ischemic stroke, and of 1.54 (1.10-2.15) for the combined endpoint compared to individuals with plasma ionized calcium within the reference interval; hypocalcemia was not associated with cardiovascular disease. In models using plasma ionized calcium as a continuous variable, the associations were nonlinear; above the median, each 0.1 mmol/L higher plasma ionized calcium was associated with a hazard ratio of 1.31(1.02-1.68) for myocardial infarction, 1.21 (0.95-1.54) for ischemic stroke, and of 1.28 (1.08-1.53) for the combined endpoint.

Conclusions: High plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke compared to plasma ionized calcium within the reference interval.
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http://dx.doi.org/10.1093/clinchem/hvaa245DOI Listing
January 2021

Very Low-Density Lipoprotein Cholesterol May Mediate a Substantial Component of the Effect of Obesity on Myocardial Infarction Risk: The Copenhagen General Population Study.

Clin Chem 2021 Jan;67(1):276-287

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.

Background: Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL) cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity.

Methods: We included 29 010 individuals free of myocardial infarction at baseline, nested within 109 751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy.

Results: Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%).

Conclusions: VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity.
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http://dx.doi.org/10.1093/clinchem/hvaa290DOI Listing
January 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Authors:
David V Conti Burcu F Darst Lilit C Moss Edward J Saunders Xin Sheng Alisha Chou Fredrick R Schumacher Ali Amin Al Olama Sara Benlloch Tokhir Dadaev Mark N Brook Ali Sahimi Thomas J Hoffmann Atushi Takahashi Koichi Matsuda Yukihide Momozawa Masashi Fujita Kenneth Muir Artitaya Lophatananon Peggy Wan Loic Le Marchand Lynne R Wilkens Victoria L Stevens Susan M Gapstur Brian D Carter Johanna Schleutker Teuvo L J Tammela Csilla Sipeky Anssi Auvinen Graham G Giles Melissa C Southey Robert J MacInnis Cezary Cybulski Dominika Wokołorczyk Jan Lubiński David E Neal Jenny L Donovan Freddie C Hamdy Richard M Martin Børge G Nordestgaard Sune F Nielsen Maren Weischer Stig E Bojesen Martin Andreas Røder Peter Iversen Jyotsna Batra Suzanne Chambers Leire Moya Lisa Horvath Judith A Clements Wayne Tilley Gail P Risbridger Henrik Gronberg Markus Aly Robert Szulkin Martin Eklund Tobias Nordström Nora Pashayan Alison M Dunning Maya Ghoussaini Ruth C Travis Tim J Key Elio Riboli Jong Y Park Thomas A Sellers Hui-Yi Lin Demetrius Albanes Stephanie J Weinstein Lorelei A Mucci Edward Giovannucci Sara Lindstrom Peter Kraft David J Hunter Kathryn L Penney Constance Turman Catherine M Tangen Phyllis J Goodman Ian M Thompson Robert J Hamilton Neil E Fleshner Antonio Finelli Marie-Élise Parent Janet L Stanford Elaine A Ostrander Milan S Geybels Stella Koutros Laura E Beane Freeman Meir Stampfer Alicja Wolk Niclas Håkansson Gerald L Andriole Robert N Hoover Mitchell J Machiela Karina Dalsgaard Sørensen Michael Borre William J Blot Wei Zheng Edward D Yeboah James E Mensah Yong-Jie Lu Hong-Wei Zhang Ninghan Feng Xueying Mao Yudong Wu Shan-Chao Zhao Zan Sun Stephen N Thibodeau Shannon K McDonnell Daniel J Schaid Catharine M L West Neil Burnet Gill Barnett Christiane Maier Thomas Schnoeller Manuel Luedeke Adam S Kibel Bettina F Drake Olivier Cussenot Géraldine Cancel-Tassin Florence Menegaux Thérèse Truong Yves Akoli Koudou Esther M John Eli Marie Grindedal Lovise Maehle Kay-Tee Khaw Sue A Ingles Mariana C Stern Ana Vega Antonio Gómez-Caamaño Laura Fachal Barry S Rosenstein Sarah L Kerns Harry Ostrer Manuel R Teixeira Paula Paulo Andreia Brandão Stephen Watya Alexander Lubwama Jeannette T Bensen Elizabeth T H Fontham James Mohler Jack A Taylor Manolis Kogevinas Javier Llorca Gemma Castaño-Vinyals Lisa Cannon-Albright Craig C Teerlink Chad D Huff Sara S Strom Luc Multigner Pascal Blanchet Laurent Brureau Radka Kaneva Chavdar Slavov Vanio Mitev Robin J Leach Brandi Weaver Hermann Brenner Katarina Cuk Bernd Holleczek Kai-Uwe Saum Eric A Klein Ann W Hsing Rick A Kittles Adam B Murphy Christopher J Logothetis Jeri Kim Susan L Neuhausen Linda Steele Yuan Chun Ding William B Isaacs Barbara Nemesure Anselm J M Hennis John Carpten Hardev Pandha Agnieszka Michael Kim De Ruyck Gert De Meerleer Piet Ost Jianfeng Xu Azad Razack Jasmine Lim Soo-Hwang Teo Lisa F Newcomb Daniel W Lin Jay H Fowke Christine Neslund-Dudas Benjamin A Rybicki Marija Gamulin Davor Lessel Tomislav Kulis Nawaid Usmani Sandeep Singhal Matthew Parliament Frank Claessens Steven Joniau Thomas Van den Broeck Manuela Gago-Dominguez Jose Esteban Castelao Maria Elena Martinez Samantha Larkin Paul A Townsend Claire Aukim-Hastie William S Bush Melinda C Aldrich Dana C Crawford Shiv Srivastava Jennifer C Cullen Gyorgy Petrovics Graham Casey Monique J Roobol Guido Jenster Ron H N van Schaik Jennifer J Hu Maureen Sanderson Rohit Varma Roberta McKean-Cowdin Mina Torres Nicholas Mancuso Sonja I Berndt Stephen K Van Den Eeden Douglas F Easton Stephen J Chanock Michael B Cook Fredrik Wiklund Hidewaki Nakagawa John S Witte Rosalind A Eeles Zsofia Kote-Jarai Christopher A Haiman

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
January 2021

Arterial hypertension and morphologic abnormalities of cardiac chambers: results from the Copenhagen General Population Study.

J Hypertens 2021 Apr;39(4):703-710

Department of Cardiology, The Heart Center, Rigshospitalet.

Objectives: In patients with arterial hypertension (AH), hypertension-mediated organ damage may be manifested by cardiac chamber enlargement and/or remodeling. Cardiac computed tomography imaging has emerged as an important method for morphological assessment of cardiac chambers. We tested the hypothesis that prevalence of cardiac chamber abnormalities is specifically related to clinical categories of AH in the general population.

Methods: We studied 4747 individuals, mean age was 60 years (range: 40-93), 46% were men, undergoing 320-detector computed tomography in the Copenhagen General Population Study. Clinical categories of AH were: normotensive (n = 2484), untreated hypertensive (n = 1301), treated controlled hypertensive (n = 412) and treated uncontrolled hypertensive (n = 550). Chamber abnormalities in the form of left ventricular (LV) concentric remodeling, LV eccentric hypertrophy, LV concentric hypertrophy or left atrial enlargement were assessed, in addition to LV or right ventricular enlargement.

Results: Chamber abnormalities were present in 23% of all individuals. Combined LV and left atrial abnormalities were rare (<2%). LV concentric remodeling (10%) was the most prevalent abnormality, and most commonly found in individuals with treated hypertension. LV and right ventricular enlargements were unrelated to hypertension. The highest frequencies of chamber abnormalities were found in individuals of elevated blood pressure (BP) with (40%) or without (32%) treatment, as opposed to individuals of normal BP with (27%) or without (14%) treatment, P less than 0.0001.

Conclusion: In a general population cohort, untreated or inadequately treated AH was associated with the highest prevalence of cardiac chamber enlargement and remodeling. These observations suggest a strong link between elevated BPs and development of hypertension-mediated organ damage.
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http://dx.doi.org/10.1097/HJH.0000000000002705DOI Listing
April 2021

Occupational exposures and exacerbations of asthma and COPD-A general population study.

PLoS One 2020 28;15(12):e0243826. Epub 2020 Dec 28.

Department of Occupational and Environmental Medicine, Bispebjerg Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: Recent studies suggest that occupational inhalant exposures trigger exacerbations of asthma and chronic obstructive pulmonary disease, but findings are conflicting.

Methods: We included 7,768 individuals with self-reported asthma (n = 3,215) and/or spirometric airflow limitation (forced expiratory volume in 1 second (FEV1)/ forced expiratory volume (FVC) <0.70) (n = 5,275) who participated in The Copenhagen City Heart Study or The Copenhagen General Population Study from 2001-2016. Occupational exposure was assigned by linking job codes with job exposure matrices, and exacerbations were defined by register data on oral corticosteroid treatment, emergency care unit assessment or hospital admission. Associations between occupational inhalant exposure each year of follow-up and exacerbation were assessed by Cox regression with time varying exposure and age as the underlying time scale.

Results: Participants were followed for a median of 4.6 years (interquartile range, IQR 5.4), during which 870 exacerbations occurred. Exacerbations were not associated with any of the selected exposures (high molecular weight sensitizers, low molecular weight sensitizers, irritants or low and high levels of mineral dust, biological dust, gases & fumes or the composite variable vapours, gases, dusts or fumes). Hazards ratios ranged from 0.8 (95% confidence interval: 0.7;1.0) to 1.2 (95% confidence interval: 0.9;1.7).

Conclusion: Exacerbations of obstructive airway disease were not associated with occupational inhalant exposures assigned by a job exposure matrix. Further studies with alternative exposure assessment are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243826PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769267PMC
February 2021

In Reply: Association between 25-Hydroxyvitamin D and Fracture Risk: A Mechanistic Point of View.

Clin Chem 2021 Jan;67(2):442-443

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

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http://dx.doi.org/10.1093/clinchem/hvaa315DOI Listing
January 2021

Low HDL (High-Density Lipoprotein) Cholesterol and High White Blood Cell Counts: A Mendelian Randomization Study.

Arterioscler Thromb Vasc Biol 2020 Dec 17:ATVBAHA120314983. Epub 2020 Dec 17.

Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte Hospital, Denmark. (M.H., K.M.P., B.G.N., S.A.).

Objective: Animal studies suggest that HDL (high-density lipoprotein) regulates proliferation and differentiation of hematopoietic stem cells. Using a Mendelian randomization approach, we tested the hypothesis that low HDL cholesterol is associated with high white blood cell counts. Approach and Results: We included 107 952 individuals aged 20 to 100 years from the Copenhagen General Population Study with information on HDL cholesterol, white blood cell counts, and 9 genetic variants associated with HDL cholesterol. In multivariable-adjusted observational analyses, HDL cholesterol was inversely associated with white blood cell counts. On a continuous scale, a 1-mmol/L (39 mg/dL) lower HDL cholesterol was associated with 5.1% (95% CI, 4.7%-5.4%) higher leukocytes, 4.5% (95% CI, 4.0%-4.9%) higher neutrophils, 5.7% (95% CI, 5.3%-6.1%) higher lymphocytes, 5.7% (95% CI, 5.3%-6.2%) higher monocytes, 14.8% (95% CI, 13.9%-15.8%) higher eosinophils, and 3.9% (95% CI, 3.1%-4.7%) higher basophils. In age- and sex-adjusted genetic analyses using the inverse-variance weighted analysis, a 1-mmol/L (39 mg/dL) genetically determined lower HDL cholesterol was associated with 2.2% (95% CI, 0.3%-4.1%) higher leukocytes, 4.3% (95% CI, 1.6%-7.1%) higher lymphocytes, 4.3% (95% CI, 2.6%-6.1%) higher monocytes, and 4.8% (95% CI, 1.2%-8.5%) higher eosinophils. Overall, the genetic associations were robust across sensitivity analyses and replicated using summary statistics from the UK Biobank with up to 350 470 individuals.

Conclusions: Genetic and hence lifelong low HDL cholesterol was associated with high peripheral blood leukocytes, including high lymphocytes, monocytes, and eosinophils. The concordance between observational and genetic estimates and independent replication suggest a potential causal relationship.
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http://dx.doi.org/10.1161/ATVBAHA.120.314983DOI Listing
December 2020

VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial Infarction Associated With apoB-Containing Lipoproteins.

J Am Coll Cardiol 2020 12;76(23):2725-2735

Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Plasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs).

Objectives: The authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins.

Methods: Nested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs).

Results: During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.

Conclusions: VLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.
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http://dx.doi.org/10.1016/j.jacc.2020.09.610DOI Listing
December 2020

Relationship between supernormal lung function and long-term risk of hospitalisations and mortality: a population-based cohort study.

Eur Respir J 2021 Apr 1;57(4). Epub 2021 Apr 1.

Dept of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

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http://dx.doi.org/10.1183/13993003.04055-2020DOI Listing
April 2021

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population.

JAMA Cardiol 2021 Mar;6(3):258-266

Section for Molecular Genetics, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Importance: Several lines of evidence support low plasma transthyretin concentration as an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown.

Objective: To evaluate whether low plasma transthyretin concentration is associated with incident HF in the general population.

Design, Setting, And Participants: This study included data from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; n = 9582) and the Copenhagen City Heart Study (CCHS; n = 7385). Using these data, first, whether low concentration of plasma transthyretin was associated with increased risk of incident HF was tested. Second, whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF was tested. Data were collected from November 2003 to March 2017 in the CGPS and from November 1991 to June 1994 in the CCHS; participants from both studies were observed for survival time end points until March 2017. Data were analyzed from March to June 2019.

Exposures: Transthyretin concentration at or below the 5th percentile, between the 5th and 95th percentile (reference), and greater than the 95th percentile; genetic variants in TTR.

Main Outcome And Measure: Incident HF identified using the Danish National Patient Registry.

Results: Of 9582 individuals in the CGPS, 5077 (53.0%) were women, and the median (interquartile range [IQR]) age was 56 (47-65) years. Of 7385 individuals in the CCHS, 4452 (60.3%) were women, and the median (IQR) age was 59 (46-70) years. During a median (IQR) follow-up of 12.6 (12.3-12.9) years and 21.7 (11.6-23.8) years, 441 individuals (4.6%) in the CGPS and 1122 individuals (15.2%) in the CCHS, respectively, developed HF. Baseline plasma transthyretin concentrations at or below the 5th percentile were associated with incident HF (CGPS: hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; CCHS: HR, 1.4; 95% CI, 1.1-1.7). Risk of HF was highest in men with low transthyretin levels. Compared with p.T139M, a transthyretin-stabilizing variant, TTR genotype was associated with stepwise lower transthyretin concentrations for wild-type TTR (-16.5%), p.G26S (-18.1%), and heterozygotes for other variants (p.V142I, p.H110N, and p.D119N; -30.8%) (P for trend <.001). The corresponding HRs for incident HF were 1.14 (95% CI, 0.57-2.28), 1.29 (95% CI, 0.64-2.61), and 2.04 (95% CI, 0.54-7.67), respectively (P for trend = .04).

Conclusions And Relevance: In this study, lower plasma and genetically determined transthyretin concentrations were associated with a higher risk of incident HF, suggesting a potential mechanistic association between low transthyretin concentration as a marker of tetramer instability and incident HF in the general population.
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http://dx.doi.org/10.1001/jamacardio.2020.5969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689572PMC
March 2021

Novel Insights From Human Studies on the Role of High-Density Lipoprotein in Mortality and Noncardiovascular Disease.

Arterioscler Thromb Vasc Biol 2021 01 24;41(1):128-140. Epub 2020 Nov 24.

Department of Clinical Biochemistry (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.

The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.
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http://dx.doi.org/10.1161/ATVBAHA.120.314050DOI Listing
January 2021

Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis.

Circulation 2021 Mar 24;143(9):921-934. Epub 2020 Nov 24.

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.

Methods: We examined the effect of a gain-of-function variant in (rs1800777, p.Arg468Gln) and a genetic score for decreased function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.

Results: A fixed-effect meta-analysis of all 7 cohorts found that the gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; <0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank =0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express (50.0% versus 42.9%, Log-rank =0.87).

Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048568DOI Listing
March 2021

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

Importance of Early COPD In Young Adults for Development of Clinical COPD: Findings from the Copenhagen General Population Study.

Am J Respir Crit Care Med 2020 Nov 3. Epub 2020 Nov 3.

The University of Manchester, 5292, Division of Infection, Immunity and Respiratory Medicine, Manchester, United Kingdom of Great Britain and Northern Ireland.

Rationale: Individuals that will develop COPD could be identified at an early age before clinical manifestations appear.

Objective: We investigated risk of Clinical COPD 10years later in young adults from the general population with and without Early COPD with a focus on smoking exposure.

Methods: We included 14,870 individuals aged 20-100 from the Copenhagen General Population Study with spirometry 10years apart. Early COPD was defined as baseline FEV1/ FVC< LLN in individuals aged<50. Outcomes included Clinical COPD at final examination 10years later (chronic respiratory symptoms with FEV1/FVC<0.70 and FEV1<80% predicted) and acute exacerbation hospitalisations during follow-up.

Results: Among 5,497 individuals aged<50 at baseline with FEV1/FVC≥0.70, 104(3%) developed Clinical COPD 10years later; 4% had Early COPD in smokers with ≥10pack-years, 3% in smokers with <10pack-years, and 2% in never-smokers. Among smokers with ≥10pack-years, 24% developed Clinical COPD in those with versus 4% in those without Early COPD. Corresponding numbers were 10% and 1% in smokers with <10pack-years, and 3% and <1% in never-smokers, respectively. Among individuals with Early COPD, odds ratios for Clinical COPD 10years later were 7.77(95%CI:4.10-14.7) in smokers with ≥10pack-years and 8.56(4.92-14.9) in all smokers, while hazard ratios for acute exacerbation hospitalisations were 4.16(95%CI:1.66-10.5) and 4.33(1.89-9.93), respectively. Results were validated in the Copenhagen City Heart Study.

Conclusions: Depending on amount of smoking exposure, less than 24% of young adults in the general population with Early COPD develop Clinical COPD 10 years later. A smoking exposure threshold for Early COPD should be re-considered, as younger individuals are less represented in those with high smoking exposure.
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http://dx.doi.org/10.1164/rccm.202003-0532OCDOI Listing
November 2020

Associations between body mass index trajectories in childhood and cardiovascular risk factors in adulthood.

Atherosclerosis 2020 12 9;314:10-17. Epub 2020 Oct 9.

Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Human Genomics and Metagenomics in Metabolism, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background And Aims: Children with a growth trajectory of overweight have higher levels of cardiovascular disease (CVD) risk factors than children with a normal-weight trajectory. However, less is known about how trajectories of body mass index (BMI) across the rest of the BMI spectrum relate to CVD risk factors and whether adult BMI affects these associations. Our aim was to examine associations between childhood BMI trajectories and adult CVD risk factors.

Methods: We included 2466 individuals with childhood weights and heights (ages 6-14) from the Copenhagen School Health Records Register and adult CVD risk factors (ages 20-81) from the Copenhagen City Heart Study. Associations between childhood BMI trajectories identified by latent class modelling and CVD risk factors were examined using generalized linear regression analyses with and without adjustment for adult BMI. Normal-weight and overweight were defined by growth references from the Centers for Disease Control and Prevention.

Results: We identified four childhood trajectories within the normal-weight spectrum and one trajectory of overweight. Compared to the trajectory with the lowest BMI level, several higher BMI trajectories were associated with worse circumference, HDL and glucose homeostasis in adulthood. The highest trajectory was additionally associated with higher total cholesterol and triglycerides. When adjusting for adult BMI, the higher BMI trajectories had lower waist circumference, blood pressure and triglycerides.

Conclusions: Trajectories of BMI within the normal-weight range and in the overweight range are associated with a worse CVD risk profile than in the lowest BMI trajectory, and these associations are modifiable by growth after childhood.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.10.011DOI Listing
December 2020