Publications by authors named "Lars Lind"

649 Publications

Plasma Protein Profile of Incident Myocardial Infarction, Ischemic Stroke, and Heart Failure in 2 Cohorts.

J Am Heart Assoc 2021 Jun 5;10(12):e017900. Epub 2021 Jun 5.

Department of Medical Sciences Uppsala University Uppsala Sweden.

Background The aim is to study common etiological pathways for 3 major cardiovascular diseases (CVD), as reflected in multiple proteins. Methods and Results Eighty-four proteins were measured using the proximity extension technique in 870 participants in the PIVUS (Prospective Investigation of Uppsala Seniors Study) cohort on 3 occasions (age 70, 75, and 80 years). The sample was followed for incident myocardial infarction, ischemic stroke or heart failure. The same proteins were measured in an independent validation sample, the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort in 595 participants at age 77. During a follow-up of up to 15 years in PIVUS and 9 years in ULSAM, 222 and 167 individuals experienced a CVD. Examining associations with the 3 outcomes separately in a meta-analysis of the 2 cohorts, 6 proteins were related to incident myocardial infarction, 25 to heart failure, and 8 proteins to ischemic stroke following adjustment for traditional risk factors. Growth differentiation factor 15 and tumor necrosis factor-related apoptosis-inducing ligand receptor 2 were related to all 3 CVDs. Including estimated glomerular filtration rate in the models attenuated some of these relationships. Fifteen proteins were related to a composite of all 3 CVDs using a discovery/validation approach when adjusting for traditional risk factors. A selection of 7 proteins by lasso in PIVUS improved discrimination of incident CVD by 7.3% compared with traditional risk factors in ULSAM. Conclusions We discovered and validated associations of multiple proteins with incident CVD. Only a few proteins were associated with all 3 diseases: myocardial infarction, ischemic stroke, and heart failure.
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http://dx.doi.org/10.1161/JAHA.120.017900DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 Jun 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Time spent outdoors and risk of myocardial infarction and stroke in middle and old aged adults: Results from the UK Biobank prospective cohort.

Environ Res 2021 Aug 19;199:111350. Epub 2021 May 19.

Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden; Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.

Background: Time spent outdoors has been previously related to several cardiovascular risk factors, implying that it may confer either beneficial or harmful effects on cardiovascular health. However, no large population-based studies have examined the relation between time spent outdoors and myocardial infarction and stroke.

Objectives: We aimed to investigate the longitudinal relation between time spent outdoors and myocardial infarction and stroke in large UK population-based cohort.

Methods: A total of 446,648 participants from UK Biobank were included in the study of which 431,146 participants (56% females and 44% males with a mean age of 56.4 ± 8.1 years) were followed for a median time of 7 years. Time spent outdoors was self-reported and participants were stratified into quantiles (less than 1.5 [reference group]; 1.5 to 2.4; 2.5 to 3.5 and more than 3.5 h per day outdoors). Myocardial infarction and stroke events were either collected from hospital records and death registries or were self-reported by the participants. Cox proportional hazard regression was used for the analysis. In addition to age and sex, analyses were adjusted for potential demographic (TDI, ethnic background, current employment status), lifestyle (alcohol intake frequency, current tobacco use, sedentary time and moderate-to-vigorous physical activity), health related factors (BMI, systolic and diastolic blood pressure) and environmental indicators (NO, NO, PM, PM, PM, noise pollution, % greenspace, % natural environment and % water).

Results: A 20% increased risk for myocardial infarction incidence was observed among participants who reported spending more than 3.5 h/day outdoors (HR: 1.20, 95% CI: 1.06-1.36) compared to the reference group. A trend was also observed for stroke (HR: 1.14, 95% CI: 0.97-1.34).

Conclusion: Findings from the present study indicate that spending more than 3.5 h/day outdoors is a risk factor for myocardial infarction and stroke. Future research is needed to further understand the relation between time spent outdoors and cardiovascular disease.
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http://dx.doi.org/10.1016/j.envres.2021.111350DOI Listing
August 2021

Systematic Coronary Risk Evaluation estimated risk and prevalent subclinical atherosclerosis in coronary and carotid arteries: A population-based cohort analysis from the Swedish Cardiopulmonary Bioimage Study.

Eur J Prev Cardiol 2021 Apr;28(3):250-259

Department of Clinical Sciences, Danderyd University Hospital, Sweden.

Background: It is not clear if the European Systematic Coronary Risk Evaluation algorithm is useful for identifying prevalent subclinical atherosclerosis in a population of apparently healthy individuals. Our aim was to explore the association between the risk estimates from Systematic Coronary Risk Evaluation and prevalent subclinical atherosclerosis.

Design: The design of this study was as a cross-sectional analysis from a population-based study cohort.

Methods: From the general population, the Swedish Cardiopulmonary Bioimage Study randomly invited individuals aged 50-64 years and enrolled 13,411 participants mean age 57 (standard deviation 4.3) years; 46% males between November 2013-December 2016. Associations between Systematic Coronary Risk Evaluation risk estimates and coronary artery calcification and plaques in the carotid arteries by using imaging data from a computed tomography of the heart and ultrasonography of the carotid arteries were examined.

Results: Coronary calcification was present in 39.5% and carotid plaque in 56.0%. In men, coronary artery calcium score >0 ranged from 40.7-65.9% and presence of carotid plaques from 54.5% to 72.8% in the age group 50-54 and 60-65 years, respectively. In women, the corresponding difference was from 17.1-38.9% and from 41.0-58.4%. A doubling of Systematic Coronary Risk Evaluation was associated with an increased probability to have coronary artery calcium score >0 (odds ratio: 2.18 (95% confidence interval 2.07-2.30)) and to have >1 carotid plaques (1.67 (1.61-1.74)).

Conclusion: Systematic Coronary Risk Evaluation estimated risk is associated with prevalent subclinical atherosclerosis in two major vascular beds in a general population sample without established cardiovascular disease or diabetes mellitus. Thus, the Systematic Coronary Risk Evaluation risk chart may be of use for estimating the risk of subclinical atherosclerosis.
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http://dx.doi.org/10.1177/2047487320909300DOI Listing
April 2021

Concentrations of nine endogenous steroid hormones in 70-year-old men and women.

Endocr Connect 2021 May 13;10(5):511-520. Epub 2021 May 13.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Objectives: Circulating concentrations of endogenous steroids have systemic implications on health in elderly. However, population-based age- and ethnicity-specific data are scarce. The aim was to report sex-specific plasma concentrations of endogenous sex and adrenal steroids in elderly Swedish Caucasians, to examine the impact of BMI and to present concentrations in apparently healthy subjects.

Methods: A population-based observational study of 70-year olds, including 684 community-dwelling men and women enrolled in the PIVUS study, Sweden. Median plasma concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for pregnenolone, 17-hydroxypregnenolone, 17-hydroxy-progesterone, 11-deoxycortisol, DHEA, androstenedione, testosterone, estrone and estradiol.

Results: Plasma concentrations were significantly higher in men (n = 452) than in women (n = 232) for estradiol: median 61.3 pmol/L (95% CI, 11.4, 142.7) vs 18.4 (4.0, 127.3), for estrone: 92.8 (33.3, 206) vs 71.6 (17.8, 209) pmol/L, and for testosterone 13.8 (5.7, 28.0) vs 0.7 (0.2, 2.0) nmol/L. Higher concentrations of estrone and estradiol were observed in obese than non-obese women. Compared to non-obese men, obese men had lower concentrations of testosterone and its precursors: 17-hydroxypregnenolone, 17-hydroxyprogesterone, androstenedione and DHEA. The subgroup of apparently healthy individuals had median values > 20% lower for estrone and estradiol in women but slightly higher for testosterone in both sexes.

Conclusions: Concentrations of estradiol, estrone and testosterone were higher in 70-year-old men than in women. BMI associated positively to estradiol and estrone in women and negatively to testosterone in men. Apparently healthy women had lower median concentrations of estradiol and estrone and men had higher median testosterone compared to all individuals.
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http://dx.doi.org/10.1530/EC-21-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183619PMC
May 2021

High Serum-Induced AhRL Is Associated with Prevalent Metabolic Syndrome and Future Impairment of Glucose Tolerance in the Elderly.

Endocrinol Metab (Seoul) 2021 Apr 19;36(2):436-446. Epub 2021 Apr 19.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: High circulating levels of dioxins and dioxin-like chemicals, acting via the aryl hydrocarbon receptor (AhR), have previously been linked to diabetes. We now investigated whether the serum AhR ligands (AhRL) were higher in subjects with metabolic syndrome (MetS) and in subjects who had developed a worsened glucose tolerance over time.

Methods: Serum AhRL at baseline was measured by a cell-based AhRL activity assay in 70-year-old subjects (n=911) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The main outcome measures were prevalent MetS and worsening of glucose tolerance over 5 years of follow-up.

Results: AhRL was significantly elevated in subjects with prevalent MetS as compared to those without MetS, following adjustment for sex, smoking, exercise habits, alcohol intake and educational level (P=0.009). AhRL at baseline was higher in subjects who developed impaired fasting glucose or diabetes at age 75 years than in those who remained normoglycemic (P=0.0081). The odds ratio (OR) of AhRL for worsening glucose tolerance over 5 years was 1.43 (95% confidence interval [CI], 1.13 to 1.81; P=0.003, continuous variables) and 2.81 (95% CI, 1.31 to 6.02; P=0.008, in the highest quartile) adjusted for sex, life style factors, body mass index, and glucose.

Conclusion: These findings support a large body of epidemiologic evidence that exposure to AhR transactivating substances, such as dioxins and dioxin-like chemicals, might be involved in the pathogenesis of MetS and diabetes development. Measurement of serum AhRL in humans can be a useful tool in predicting the onset of metabolic disorders.
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http://dx.doi.org/10.3803/EnM.2020.883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090465PMC
April 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

Albumin Urinary Excretion Is Associated with Increased Levels of Urinary Chemokines, Cytokines, and Growth Factors Levels in Humans.

Biomolecules 2021 Mar 8;11(3). Epub 2021 Mar 8.

Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.
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http://dx.doi.org/10.3390/biom11030396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000571PMC
March 2021

Sleep duration is associated with protein biomarkers for cardiometabolic health: A large-scale population study.

J Sleep Res 2021 Mar 9:e13284. Epub 2021 Mar 9.

Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Sleep problems and short sleep duration have been linked to adverse health effects, such as cardiovascular disease and diabetes, but the mechanisms are not fully understood. Finding biomarkers could explain mechanistic pathways and help in understanding relationships between sleep and cardiometabolic health. The aim was to assess if sleep duration and sleep quality affect the cardiometabolic-related protein profile. In total, 242 proteins related to cardiometabolic health were measured in 2,430 plasma samples (male:female ratio 1:1, aged 45-75 years) from the population-based EpiHealth cohort, using a proximity extension assay. The association of self-reported sleep duration and sleep quality with each of the 242 proteins (primary outcome) was assessed with linear regression modelling, adjusting for confounders, and corrected for multiple testing using the false discovery rate (5%). Potential effect modification of age and sex was also tested using an interaction term. We identified U-shaped associations between sleep duration and the plasma levels of the proteins follistatin (more prominent in younger individuals), matrix metallopeptidase 9 (men only), urokinase receptor, adrenomedullin and kidney injury molecule, all previously known to be related to cardiovascular risk. There was no relationship between sleep quality and any of the proteins, after adjustment for confounders. These results give new leads to investigate the potential mechanistic pathways between sleep and cardiometabolic health.
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http://dx.doi.org/10.1111/jsr.13284DOI Listing
March 2021

Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study.

EBioMedicine 2021 Mar 9;65:103264. Epub 2021 Mar 9.

The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Background: It is commonly accepted that in obesity free fatty acids (FFA) cause insulin resistance and hyperglycemia, which drives hyperinsulinemia. However, hyperinsulinemia is observed in subjects with normoglycaemia and thus the paradigm above should be reevaluated.

Methods: We describe two studies: MD-Lipolysis, a case control study investigating the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics; and POEM, a cohort study used for validating differences in circulating metabolites in relation to adiposity and insulin resistance observed in the MD-Lipolysis study.

Findings: In insulin-resistant obese with normal glycaemia from the MD-Lipolysis study, hyperinsulinemia was associated with elevated FFA. Lipolysis, assessed by glycerol release per adipose tissue mass or adipocyte surface, was similar between obese and lean individuals. Adipose tissue from obese subjects showed reduced expression of genes mediating catecholamine-driven lipolysis, lipid storage, and increased expression of genes driving hyperplastic growth. In the POEM study, FFA levels were specifically elevated in obese-overweight subjects with normal fasting glucose and high fasting levels of insulin and C-peptide.

Interpretation: In obese subjects with normal glycaemia elevated circulating levels of FFA at fasting are the major metabolic derangement candidate driving fasting hyperinsulinemia. Elevated FFA in obese with normal glycaemia were better explained by increased fat mass rather than by adipose tissue insulin resistance. These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA.

Funding: Swedish-Research-Council (2016-02660); Diabetesfonden (DIA2017-250; DIA2018-384; DIA2020-564); Novo-Nordisk-Foundation (NNF17OC0027458; NNF19OC0057174); Cancerfonden (CAN2017/472; 200840PjF); Swedish-ALF-agreement (2018-74560).
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http://dx.doi.org/10.1016/j.ebiom.2021.103264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992078PMC
March 2021

Relative and Absolute Risk to Guide the Management of Pulse Pressure, an Age-Related Cardiovascular Risk Factor.

Am J Hypertens 2021 Mar 4. Epub 2021 Mar 4.

Laboratory of Neurosciences, Faculty of Medicine, University of Zulia, Maracaibo, Zulia, Venezuela.

Background: Pulse pressure (PP) reflects the age-related stiffening of the central arteries, but no study addressed the management of the PP-related risk over the human lifespan.

Methods: In 4663 young (18-49 years) and 7185 older adults (≥50 years), brachial PP was recorded over 24-hour. Total mortality and all major cardiovascular events combined (MACE) were co-primary endpoints. Cardiovascular death, coronary events and stroke were secondary endpoints.

Results: In young adults (median follow-up, 14.1 years; mean PP, 45.1 mmHg), greater PP was not associated with absolute risk; the endpoint rates were ≤2.01 per 1000 person-years. The adjusted hazard ratios expressed per 10mmHg PP increments were less than unity (P≤0.027) for MACE (0.67; 95% CI, 0.47-0.96) and cardiovascular death (0.33; 95% CI, 0.11-0.75). In older adults (median follow-up, 13.1 years; mean PP, 52.7 mmHg), the endpoint rates, expressing absolute risk, ranged from 22.5 to 45.4 per 1000 person-years and the adjusted hazard ratios, reflecting relative risk, from 1.09 to 1.54 (P<0.0001). The PPrelated relative risks of death, MACE and stroke decreased >3-fold from age 55 to 75 years, whereas absolute risk rose by a factor 3.

Conclusions: From 50 years onwards, the PP-related relative risk decreases, whereas absolute risk increases. From a lifecourse perspective, young adulthood provides a window of opportunity to manage risk factors and prevent target organ damage as forerunner of premature death and MACE. In older adults, treatment should address absolute risk, thereby extending life in years and quality.
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http://dx.doi.org/10.1093/ajh/hpab048DOI Listing
March 2021

n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies.

Diabetes Care 2021 May 3;44(5):1133-1142. Epub 2021 Mar 3.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.

Research Design And Methods: For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.

Results: A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.

Conclusions: Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.
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http://dx.doi.org/10.2337/dc20-2426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132316PMC
May 2021

Life-Time Covariation of Major Cardiovascular Diseases: A 40-Year Longitudinal Study and Genetic Studies.

Circ Genom Precis Med 2021 Apr 26;14(2):e002963. Epub 2021 Feb 26.

Uppsala Clinical Research Centre (UCR) (E.L.), Uppsala University, Sweden.

Background: It is known that certain cardiovascular diseases (CVD) are associated, like atrial fibrillation and stroke. However, for other CVDs, the links and temporal trends are less studied. In this longitudinal study, we have investigated temporal epidemiological and genetic associations between different CVDs.

Methods: The ULSAM (Uppsala Longitudinal Study of Adult Men; 2322 men aged 50 years) has been followed for 40 years regarding 4 major CVDs (incident myocardial infarction, ischemic stroke, heart failure, and atrial fibrillation). For the genetic analyses, publicly available data were used.

Results: Using multistate modeling, significant relationships were seen between pairs of all of the 4 investigated CVDs. However, the risk of obtaining one additional CVD differed substantially both between different CVDs and between their temporal order. The relationship between heart failure and atrial fibrillation showed a high risk ratio (risk ratios, 24-26) regardless of the temporal order. A consistent association was seen also for myocardial infarction and atrial fibrillation but with a lower relative risk (risk ratios, 4-5). In contrast, the risk of receiving a diagnosis of heart failure following a myocardial infarction was almost twice as high as for the reverse temporal order (risk ratios, 16 versus 9). Genetic loci linked to traditional risk factors could partly explain the observed associations between the CVDs, but pathway analyses disclosed also other pathophysiological links.

Conclusions: During 40 years, all of the 4 investigated CVDs were pairwise associated with each other regardless of the temporal order of occurrence, but the risk magnitude differed between different CVDs and their temporal order. Genetic analyses disclosed new pathophysiological links between CVDs.
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http://dx.doi.org/10.1161/CIRCGEN.120.002963DOI Listing
April 2021

Relationships between plasma levels and six proinflammatory interleukins and body composition using a new magnetic resonance imaging voxel-based technique.

Cytokine X 2021 Mar 21;3(1):100050. Epub 2020 Dec 21.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Background: Obesity has previously been linked to inflammation. Here we investigated how plasma levels of six interleukins were related to body fat distribution.

Methods: In 321 subjects, all aged 50 years, in the population-based POEM study (mean BMI 26-27 kg/m), six interleukins were measured together with a DXA scan for determination of fat and lean mass. Also a whole-body magnetic resonance imaging (MRI) scan, in which fat content measurements were acquired in > 1 million voxels was performed. Interleukin levels were related to each of these voxels by the voxel-based technique "Imiomics" to create a 3D-view of how these measurements were related to size of each part of the body.

Results: Levels of IL-1RA and IL-6 were related to traditional DXA and MRI measurements of adipose tissue at all locations. Neither IL-6R, nor IL-8 or IL-18, showed any consistent significant relationships vs the traditional measurements of body composition, while IL-16 showed relationships being of borderline significance. The Imiomics evaluation further strengthen the view that IL-1RA and IL-6 were related to subcutaneous adipose tissue (SAT), as well to ectopic fat distribution. In women, IL-16 levels were weakly related to expansion of SAT in the upper part of the body, while on the contrary, IL-8 levels were related to a reduction of SAT volume.

Conclusion: Of the six evaluated interleukins, plasma IL-1RA and IL-6 levels were related to the amount of adipose tissue in all parts of the body, while a diverse picture was seen for other interleukins, suggesting that different interleukins are related to fat distribution in different ways.
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http://dx.doi.org/10.1016/j.cytox.2020.100050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885882PMC
March 2021

Reverse Dipping of Systolic Blood Pressure Is Associated With Increased Dementia Risk in Older Men: A Longitudinal Study Over 24 Years.

Hypertension 2021 Apr 8;77(4):1383-1390. Epub 2021 Feb 8.

Department of Neuroscience (X.T., C.B.), Uppsala University, Sweden.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16711DOI Listing
April 2021

A longitudinal study over 40 years to study the metabolic syndrome as a risk factor for cardiovascular diseases.

Sci Rep 2021 Feb 3;11(1):2978. Epub 2021 Feb 3.

Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

The impact of most, but not all, cardiovascular risk factors decline by age. We investigated how the metabolic syndrome (MetS) was related to cardiovascular disease (CVD) during 40 years follow-up in the Uppsala Longitudinal Study of Adult Men (ULSAM, 2,123 men all aged 50 at baseline with reinvestigations at age 60, 70, 77 and 82). The strength of MetS as a risk factor of incident combined end-point of three outcomes (CVD) declined with ageing, as well as for myocardial infarction, ischemic stroke and heart failure when analysed separately. For CVD, the risk ratio declined from 2.77 (95% CI 1.90-4.05) at age 50 to 1.30 (95% CI 1.05-1.60) at age 82. In conclusion, the strength of MetS as a risk factor of incident CVD declined with age. Since MetS was significantly related to incident CVD also at old age, our findings suggest that the occurrence of MetS in the elderly should not be regarded as innocent. However, since our data were derived in an observational study, any impact of MetS in the elderly needs to be verified in a randomized clinical intervention trial.
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http://dx.doi.org/10.1038/s41598-021-82398-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858618PMC
February 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Multicohort Metabolomics Analysis Discloses 9-Decenoylcarnitine to Be Associated With Incident Atrial Fibrillation.

J Am Heart Assoc 2021 Jan 5;10(2):e017579. Epub 2021 Jan 5.

Division of Family Medicine and Primary Care Department of Neurobiology, Care Sciences and Society Karolinska Institutet Huddinge Sweden.

Background The molecular mechanisms involved in atrial fibrillation are not well known. We used plasma metabolomics to investigate if we could identify novel biomarkers and pathophysiological pathways of incident atrial fibrillation. Methods and Results We identified 200 endogenous metabolites in plasma/serum by nontargeted ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry in 3 independent population-based samples (TwinGene, n=1935, mean age 68, 43% females; PIVUS [Prospective Investigation of the Vasculature in Uppsala Seniors], n=897, mean age 70, 51% females; and ULSAM [Uppsala Longitudinal Study of Adult Men], n=1118, mean age 71, all males), with available data on incident atrial fibrillation during 10 to 12 years of follow-up. A meta-analysis of ULSAM and PIVUS was used as a discovery sample and TwinGene was used for validation. In PIVUS, we also investigated associations between metabolites of interest and echocardiographic indices of myocardial geometry and function. Genome-wide association studies were performed in all 3 cohorts for metabolites of interest. In the meta-analysis of PIVUS and ULSAM with 430 incident cases, 4 metabolites were associated with incident atrial fibrillation at a false discovery rate <5%. Of those, only 9-decenoylcarnitine was associated with incident atrial fibrillation and replicated in the TwinGene sample (288 cases) following adjustment for traditional risk factors (hazard ratio, 1.24 per unit; 95% CI, 1.06-1.45, =0.0061). A meta-analysis of all 3 cohorts disclosed another 4 significant metabolites. In PIVUS, 9-decenoylcarnitine was related to left atrium size and left ventricular mass. A Mendelian randomization analysis did not suggest a causal role of 9-decenoylcarnitine in atrial fibrillation. Conclusions A nontargeted metabolomics analysis disclosed 1 novel replicated biomarker for atrial fibrillation, 9-Decenoylcarnitine, but this acetylcarnitine is likely not causally related to atrial fibrillation.
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http://dx.doi.org/10.1161/JAHA.120.017579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955307PMC
January 2021

Plasma proteomics and lung function in four community-based cohorts.

Respir Med 2021 01 5;176:106282. Epub 2020 Dec 5.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, Huddinge, Sweden; Region Dalarna, Falun, Sweden; School of Health and Social Sciences, Dalarna University, Falun, Sweden. Electronic address:

Background: Underlying mechanism leading to impaired lung function are incompletely understood.

Objectives: To investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function.

Methods: We used four community-based studies (n = 2552) to investigate associations between 79 cardiovascular/inflammatory proteins and forced expiratory volume in 1 s percent predicted (FEV%) assessed by spirometry. We divided the cohorts into discovery and replication samples and used risk factor-adjusted linear regression corrected for multiple comparison (false discovery rate of 5%). We performed Mendelian randomization analyses using genetic and spirometry data from the UK Biobank (n = 421,986) to assess causality.

Measurements And Main Results: In cross-sectional analysis, 22 proteins were associated with lower FEV% in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV%. In longitudinal analyses (n = 681), higher plasma levels of growth differentiation factor 15 (GDF-15) and interleukin 6 (IL-6) predicted a more rapid 5-year decline in lung function (change in FEV% per standard deviation of protein level -1.4, (95% CI, -2.5 to -0.3) for GDF-15, and -0.8, (95% CI, -1.5 to -0.2) for IL-6. Mendelian randomization analysis in UK-biobank provided support for a causal effect of increased GDF-15 levels and reduced FEV%.

Conclusions: Our combined approach identified GDF-15 as a potential causal factor in the development of impaired lung function in the general population. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function.
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http://dx.doi.org/10.1016/j.rmed.2020.106282DOI Listing
January 2021

Association of Fatal and Nonfatal Cardiovascular Outcomes With 24-Hour Mean Arterial Pressure.

Hypertension 2021 Jan 8;77(1):39-48. Epub 2020 Dec 8.

From the Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium (J.D.M., W.-Y. Y, L.T., F.-F.W., J.A.S., Z.-Y.Z.).

Major adverse cardiovascular events are closely associated with 24-hour blood pressure (BP). We determined outcome-driven thresholds for 24-hour mean arterial pressure (MAP), a BP index estimated by oscillometric devices. We assessed the association of major adverse cardiovascular events with 24-hour MAP, systolic BP (SBP), and diastolic BP (DBP) in a population-based cohort (n=11 596). Statistics included multivariable Cox regression and the generalized R statistic to test model fit. Baseline office and 24-hour MAP averaged 97.4 and 90.4 mm Hg. Over 13.6 years (median), 2034 major adverse cardiovascular events occurred. Twenty-four-hour MAP levels of <90 (normotension, n=6183), 90 to <92 (elevated MAP, n=909), 92 to <96 (stage-1 hypertension, n=1544), and ≥96 (stage-2 hypertension, n=2960) mm Hg yielded equivalent 10-year major adverse cardiovascular events risks as office MAP categorized using 2017 American thresholds for office SBP and DBP. Compared with 24-hour MAP normotension, hazard ratios were 0.96 (95% CI, 0.80-1.16), 1.32 (1.15-1.51), and 1.77 (1.59-1.97), for elevated and stage-1 and stage-2 hypertensive MAP. On top of 24-hour MAP, higher 24-hour SBP increased, whereas higher 24-hour DBP attenuated risk (<0.001). Considering the 24-hour measurements, R statistics were similar for SBP (1.34) and MAP (1.28), lower for DBP than for MAP (0.47), and reduced to null, if the base model included SBP and DBP; if the ambulatory BP indexes were dichotomized according to the 2017 American guideline and the proposed 92 mm Hg for MAP, the R values were 0.71, 0.89, 0.32, and 0.10, respectively. In conclusion, the clinical application of 24-hour MAP thresholds in conjunction with SBP and DBP refines risk estimates.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720872PMC
January 2021

The associations between p,p'-DDE levels and plasma levels of lipoproteins and their subclasses in an elderly population determined by analysis of lipoprotein content.

Lipids Health Dis 2020 Dec 7;19(1):249. Epub 2020 Dec 7.

Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA, 95616, USA.

Background: Lipoproteins at aberrant levels are known to play a role in cardiovascular disease. The metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), physically associates with lipids and accumulates in adipose tissue. Little is known about which lipoproteins associate with p,p'-DDE. An association between p,p'-DDE exposure and altered levels of circulating lipids was assessed in a large human cohort using a detailed analysis of lipoprotein content.

Methods: Plasma samples were collected from the subset of 75-year old Swedes in the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) cohort who were not prescribed lipid lowering medication (n = 571). p,p'-DDE concentrations in plasma were measured using high-throughput solid phase extraction and gas chromatography-high resolution mass spectrometry. Analysis of plasma lipoprotein content was performed with nuclear magnetic resonance spectroscopy.

Results: Detectable levels of p,p'-DDE were found in the plasma samples of all subjects. Elevated p,p'-DDE levels were associated with increased concentrations of lipoproteins of all diameters, with the exception of high density lipoprotein (HDL) of diameters between 14.3 nm-10.9 nm. Of the lipoprotein constituents, triglycerides were most uniformly associated with elevated p,p'-DDE across lipoproteins. p,p'-DDE was furthermore associated with apolipoprotein B, but not apolipoprotein A1.

Conclusions: The positive associations observed between each lipoprotein class and elevated p,p'-DDE support previous data suggesting that p,p'-DDE interacts with lipoproteins within plasma. It is speculated that both physio-chemical and biological mechanisms may explain why p,p'-DDE does not uniformly associate with lipids across lipoproteins.
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http://dx.doi.org/10.1186/s12944-020-01417-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722417PMC
December 2020

The impact of body mass index, central obesity and physical activity on lung function: results of the EpiHealth study.

ERJ Open Res 2020 Oct 2;6(4). Epub 2020 Nov 2.

Dept of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.

Study Objectives: Obesity is often associated with lower lung function; however, the interaction of lung function with central obesity and physical inactivity is less clear. As such, we investigated the effect on lung function of body size (body mass index (BMI)), central obesity (waist circumference (WC)) and self-reported physical activity.

Methods: Lung function, height, weight and WC were measured in 22 743 participants (12 791 women), aged 45-75 years, from the EpiHealth cohort study. Physical activity, gender and educational level were assessed using a questionnaire.

Results: Obesity, central obesity and physical inactivity were all associated with lower forced expiratory volume in 1 s (FEV) and forced vital capacity (FVC). However, in participants without central obesity there was an increase in both FEV and FVC by BMI (% predicted FVC increasing from median 98%, interquartile range (IQR) 89-110% in underweight participants (BMI <20) to 103%, IQR 94-113% in obese participants (BMI ≥30)). In contrast, there was a decrease in % predicted FVC in participants with central obesity (from 98%, IQR 89-109% in the normal weight group to 95%, IQR 85-105% in the obese weight group). We further found a negative association between physical activity and lung function among those with low and high levels of physical activity (% predicted FEV 97%, IQR 86-107% 103%, IQR 94-113%, respectively and % predicted FVC 96%, IQR 85-106% 103%, IQR 94-113%, respectively). All results remained when calculated by z-scores.

Conclusions: The association between BMI and lung function is dependent on the presence of central obesity. Independent of obesity, there is an association between physical activity and lung function.
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http://dx.doi.org/10.1183/23120541.00214-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682662PMC
October 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

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

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Cardiovascular-related proteins and the abdominal visceral to subcutaneous adipose tissue ratio.

Nutr Metab Cardiovasc Dis 2021 02 17;31(2):532-539. Epub 2020 Sep 17.

Section of Radiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Antaros Medical AB, BioVenture Hub, Mölndal, Sweden. Electronic address:

Background And Aims: An increased amount of visceral adipose tissues has been related to atherosclerosis and future cardiovascular events. The present study aims to investigate how the abdominal fat distribution links to plasma levels of cardiovascular-related proteins.

Method And Results: In the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 326, all aged 50 years), abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue volumes were quantified by MRI. Eighty-six cardiovascular-related proteins were measured by the proximity extension assay (PEA). Similar investigations were carried out in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 400, all aged 75 years). In the discovery dataset (POEM), 10 proteins were related to the VAT/SAT-ratio using false discovery rate <.05. Of those, Cathepsin D (CTSD), Interleukin-1 receptor antagonist protein (IL-1RA) and Growth hormone (GH) (inversely) were related to the VAT/SAT-ratio in the validation in PIVUS following adjustment for sex, BMI, smoking, education level and exercise habits (p < 0.05). In a secondary analysis, a meta-analysis of the two samples suggested that 15 proteins could be linked to the VAT/SAT-ratio following adjustment as above and Bonferroni-correction of the p-value.

Conclusion: Three cardiovascular-related proteins, cathepsin D, IL-1RA and growth hormone, were being associated with the distribution of abdominal adipose tissue using a discovery/validation approach. A meta-analysis of the two samples suggested that also a number of other cardiovascular-related proteins could be associated with an unfavorable abdominal fat distribution.
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http://dx.doi.org/10.1016/j.numecd.2020.09.010DOI Listing
February 2021

Commonly used clinical chemistry tests as mortality predictors: Results from two large cohort studies.

PLoS One 2020 5;15(11):e0241558. Epub 2020 Nov 5.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.

Background: The normal ranges for clinical chemistry tests are usually defined by cut-offs given by the distribution in healthy individuals. This approach does however not indicate if individuals outside the normal range are more prone to disease.

Methods: We studied the associations and risk prediction of 11 plasma and serum biomarkers with all-cause mortality in two population-based cohorts: a Swedish cohort (X69) initiated in 1969, and the UK Biobank (UKB) initiated in 2006-2010, with up to 48- and 9-years follow-up, respectively.

Results: In X69 and in UKB, 18,529 and 425,264 individuals were investigated, respectively. During the follow-up time, 14,475 deaths occurred in X69 and 17,116 in UKB. All evaluated tests were associated with mortality in X69 (P<0.0001, except bilirubin P<0.005). For calcium, blood urea nitrogen, bilirubin, hematocrit, uric acid, and iron, U-shaped associations were seen (P<0.0001). For leukocyte count, gamma-glutamyl transferase, alkaline phosphatases and lactate dehydrogenase, linear positive associations were seen, while for albumin the association was negative. Similar associations were seen in UKB. Addition of all biomarkers to a model with classical risk factors improved mortality prediction (delta C-statistics: +0.009 in X69 and +0.023 in UKB, P<0.00001 in both cohorts).

Conclusions: Commonly used clinical chemistry tests were associated with all-cause mortality both in the medium- and long-term perspective, and improved mortality prediction beyond classical risk factors. Since both linear and U-shaped relationships were found, we propose to define the normal range of a clinical chemistry test based on its association with mortality, rather than from the distribution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241558PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644047PMC
December 2020

The Plasma Metabolomic Profile is Differently Associated with Liver Fat, Visceral Adipose Tissue, and Pancreatic Fat.

J Clin Endocrinol Metab 2021 Jan;106(1):e118-e129

BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Context: Metabolic differences between ectopic fat depots may provide novel insights to obesity-related diseases.

Objective: To investigate the plasma metabolomic profiles in relation to visceral adipose tissue (VAT) volume and liver and pancreas fat percentages.

Design: Cross-sectional.

Setting: Multicenter at academic research laboratories.

Patients: Magnetic resonance imaging (MRI) was used to assess VAT volume, the percentage of fat in the liver and pancreas (proton density fat fraction [PDFF]) at baseline in 310 individuals with a body mass index ≥ 25 kg/m2 and with serum triglycerides ≥ 1.7 mmol/l and/or type 2 diabetes screened for inclusion in the 2 effect of omega-3 carboxylic acid on liver fat content studies.

Intervention: None.

Main Outcome Measure: Metabolomic profiling with mass spectroscopy enabled the determination of 1063 plasma metabolites.

Results: Thirty metabolites were associated with VAT volume, 31 with liver PDFF, and 2 with pancreas PDFF when adjusting for age, sex, total body fat mass, and fasting glucose. Liver PDFF and VAT shared 4 metabolites, while the 2 metabolites related to pancreas PDFF were unique. The top metabolites associated with liver PDFF were palmitoyl-palmitoleoyl-GPC (16:0/16:1), dihydrosphingomyelin (d18:0/22:0), and betaine. The addition of these metabolites to the Liver Fat Score improved C-statistics significantly (from 0.776 to 0.861, P = 0.0004), regarding discrimination of liver steatosis.

Conclusion: Liver PDFF and VAT adipose tissue shared several metabolic associations, while those were not shared with pancreatic PDFF, indicating partly distinct metabolic profiles associated with different ectopic fat depots. The addition of 3 metabolites to the Liver Fat Score improved the prediction of liver steatosis.
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http://dx.doi.org/10.1210/clinem/dgaa693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765636PMC
January 2021

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
October 2020