Publications by authors named "Evangelos Evangelou"

191 Publications

Umbrella Reviews: What They Are and Why We Need Them.

Methods Mol Biol 2022 ;2345:135-146

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

Evidence in clinical research is accumulating and scientific publications have increased exponentially in the last decade across all disciplines. Available information should be critically assessed. Here, we focus on umbrella reviews, an approach that systematically collects and evaluates information from multiple systematic reviews and meta-analyses. To facilitate the design and the conduct of such a study, we provide a step-by-step guide on how to perform an umbrella review. We also present ways to report the summary findings, we describe various proposed grading criteria, and we discuss potential limitations.
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http://dx.doi.org/10.1007/978-1-0716-1566-9_8DOI Listing
January 2022

Prevalence and Determinants of Sex-Specific Dietary Supplement Use in a Greek Cohort.

Nutrients 2021 Aug 20;13(8). Epub 2021 Aug 20.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece.

We describe the profile of dietary supplement use and its correlates in the Epirus Health Study cohort, which consists of 1237 adults (60.5% women) residing in urban north-west Greece. The association between dietary supplement use and demographic characteristics, lifestyle behaviors, personal medical history and clinical measurements was assessed using logistic regression models, separately for women and men. The overall prevalence of dietary supplement use was 31.4%, and it was higher in women (37.3%) compared to men (22.4%; -value = 4.2). Based on multivariable logistic regression models, dietary supplement use in women was associated with age (positively until middle-age and slightly negatively afterwards), the presence of a chronic health condition (OR = 1.71; 95% CI, 1.18-2.46), lost/removed teeth (OR = 0.52; 95% CI, 0.35-0.78) and diastolic blood pressure (OR per 5 mmHg increase =0.84; 95% CI, 0.73-0.96); body mass index and worse general health status were borderline inversely associated. In men, dietary supplement use was positively associated with being employed (OR = 2.53; 95% CI, 1.21-5.29). A considerable proportion of our sample used dietary supplements, and the associated factors differed between women and men.
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http://dx.doi.org/10.3390/nu13082857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399686PMC
August 2021

Validity of observational evidence on putative risk and protective factors: appraisal of 3744 meta-analyses on 57 topics.

BMC Med 2021 07 6;19(1):157. Epub 2021 Jul 6.

Meta-Research Innovation Center at Stanford (METRICS), Stanford, CA, 94305, USA.

Background: The validity of observational studies and their meta-analyses is contested. Here, we aimed to appraise thousands of meta-analyses of observational studies using a pre-specified set of quantitative criteria that assess the significance, amount, consistency, and bias of the evidence. We also aimed to compare results from meta-analyses of observational studies against meta-analyses of randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.

Methods: We retrieved from PubMed (last update, November 19, 2020) umbrella reviews including meta-analyses of observational studies assessing putative risk or protective factors, regardless of the nature of the exposure and health outcome. We extracted information on 7 quantitative criteria that reflect the level of statistical support, the amount of data, the consistency across different studies, and hints pointing to potential bias. These criteria were level of statistical significance (pre-categorized according to 10, 0.001, and 0.05 p-value thresholds), sample size, statistical significance for the largest study, 95% prediction intervals, between-study heterogeneity, and the results of tests for small study effects and for excess significance.

Results: 3744 associations (in 57 umbrella reviews) assessed by a median number of 7 (interquartile range 4 to 11) observational studies were eligible. Most associations were statistically significant at P < 0.05 (61.1%, 2289/3744). Only 2.6% of associations had P < 10, ≥1000 cases (or ≥20,000 participants for continuous factors), P < 0.05 in the largest study, 95% prediction interval excluding the null, and no large between-study heterogeneity, small study effects, or excess significance. Across the 57 topics, large heterogeneity was observed in the proportion of associations fulfilling various quantitative criteria. The quantitative criteria were mostly independent from one another. Across 62 associations assessed in both RCTs and in observational studies, 37.1% had effect estimates in opposite directions and 43.5% had effect estimates differing beyond chance in the two designs. Across 94 comparisons assessed in both MR and observational studies, such discrepancies occurred in 30.8% and 54.7%, respectively.

Conclusions: Acknowledging that no gold-standard exists to judge whether an observational association is genuine, statistically significant results are common in observational studies, but they are rarely convincing or corroborated by randomized evidence.
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http://dx.doi.org/10.1186/s12916-021-02020-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259334PMC
July 2021

A Body Shape Index (ABSI), hip index, and risk of cancer in the UK Biobank cohort.

Cancer Med 2021 Aug 1;10(16):5614-5628. Epub 2021 Jul 1.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, UK.

Abdominal size is associated positively with the risk of some cancers but the influence of body mass index (BMI) and gluteofemoral size is unclear because waist and hip circumference are strongly correlated with BMI. We examined associations of 33 cancers with A Body Shape Index (ABSI) and hip index (HI), which are independent of BMI by design, and compared these with waist and hip circumference, using multivariable Cox proportional hazards models in UK Biobank. During a mean follow-up of 7 years, 14,682 incident cancers were ascertained in 200,289 men and 12,965 cancers in 230,326 women. In men, ABSI was associated positively with cancers of the head and neck (hazard ratio HR = 1.14; 95% confidence interval 1.03-1.26 per one standard deviation increment), esophagus (adenocarcinoma, HR = 1.27; 1.12-1.44), gastric cardia (HR = 1.31; 1.07-1.61), colon (HR = 1.18; 1.10-1.26), rectum (HR = 1.13; 1.04-1.22), lung (adenocarcinoma, HR = 1.16; 1.03-1.30; squamous cell carcinoma [SCC], HR = 1.33; 1.17-1.52), and bladder (HR = 1.15; 1.04-1.27), while HI was associated inversely with cancers of the esophagus (adenocarcinoma, HR = 0.89; 0.79-1.00), gastric cardia (HR = 0.79; 0.65-0.96), colon (HR = 0.92; 0.86-0.98), liver (HR = 0.86; 0.75-0.98), and multiple myeloma (HR = 0.86; 0.75-1.00). In women, ABSI was associated positively with cancers of the head and neck (HR = 1.27; 1.10-1.48), esophagus (SCC, HR = 1.37; 1.07-1.76), colon (HR = 1.08; 1.01-1.16), lung (adenocarcinoma, HR = 1.17; 1.06-1.29; SCC, HR = 1.40; 1.20-1.63; small cell, HR = 1.39; 1.14-1.69), kidney (clear-cell, HR = 1.25; 1.03-1.50), and post-menopausal endometrium (HR = 1.11; 1.02-1.20), while HI was associated inversely with skin SCC (HR = 0.91; 0.83-0.99), post-menopausal kidney cancer (HR = 0.77; 0.67-0.88), and post-menopausal melanoma (HR = 0.90; 0.83-0.98). Unusually, ABSI was associated inversely with melanoma in men (HR = 0.89; 0.82-0.96) and pre-menopausal women (HR = 0.77; 0.65-0.91). Waist and hip circumference reflected associations with BMI, when examined individually, and provided biased risk estimates, when combined with BMI. In conclusion, preferential positive associations of ABSI or inverse of HI with several major cancers indicate an important role of factors determining body shape in cancer development.
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http://dx.doi.org/10.1002/cam4.4097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366087PMC
August 2021

A genome-wide scan for pleiotropy between bone mineral density and nonbone phenotypes.

Bone Res 2020 Jul 1;8(1):26. Epub 2020 Jul 1.

Department of Hygiene and Epidemiology, Clinical and Molecular Epidemiology Unit, School of Medicine, University of Ioannina, Ioannina, Greece.

Osteoporosis is the most common metabolic bone disorder globally and is characterized by skeletal fragility and microarchitectural deterioration. Genetic pleiotropy occurs when a single genetic element is associated with more than one phenotype. We aimed to identify pleiotropic loci associated with bone mineral density (BMD) and nonbone phenotypes in genome-wide association studies. In the discovery stage, the NHGRI-EBI Catalog was searched for genome-wide significant associations (P value < 5 × 10), excluding bone-related phenotypes. SNiPA was used to identify proxies of the significantly associated single nucleotide polymorphisms (SNPs) (r = 1). We then assessed putative genetic associations of this set of SNPs with femoral neck (FN) and lumbar spine (LS) BMD data from the GEFOS Consortium. Pleiotropic variants were claimed at a false discovery rate < 1.4 × 10 for FN-BMD and < 1.5 × 10 for LS-BMD. Replication of these genetic markers was performed among more than 400 000 UK Biobank participants of European ancestry with available genetic and heel bone ultrasound data. In the discovery stage, 72 BMD-related pleiotropic SNPs were identified, and 12 SNPs located in 11 loci on 8 chromosomes were replicated in the UK Biobank. These SNPs were associated, in addition to BMD, with 14 different phenotypes. Most pleiotropic associations were exhibited by rs479844 (AP5B1, OVOL1 genes), which was associated with dermatological and allergic diseases, and rs4072037 (MUC1 gene), which was associated with magnesium levels and gastroenterological cancer. In conclusion, 12 BMD-related genome-wide significant SNPs showed pleiotropy with nonbone phenotypes. Pleiotropic associations can deepen the genetic understanding of bone-related diseases by identifying shared biological mechanisms with other diseases or traits.
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http://dx.doi.org/10.1038/s41413-020-0101-8DOI Listing
July 2020

Prognostic factors for adverse outcomes in patients with COVID-19: a field-wide systematic review and meta-analysis.

Eur Respir J 2021 Jun 25. Epub 2021 Jun 25.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

Introduction: The individual prognostic factors for COVID-19 are unclear. For this reason, we aimed to present a state-of-the-art systematic review and meta-analysis on the prognostic factors for adverse outcomes in COVID-19 patients.

Methods: We systematically reviewed PubMed from January 1, 2020 to July 26, 2020 to identify non-overlapping studies examining the association of any prognostic factor with any adverse outcome in patients with COVID-19. Random-effects meta-analysis was performed, and between-study heterogeneity was quantified using I metric. Presence of small-study effects was assessed by applying the Egger's regression test.

Results: We identified 428 eligible articles, which were used in a total of 263 meta-analyses examining the association of 91 unique prognostic factors with 11 outcomes. Angiotensin-converting enzyme inhibitors, obstructive sleep apnea, pharyngalgia, history of venous thromboembolism, sex, coronary heart disease, cancer, chronic liver disease, chronic obstructive pulmonary disease, dementia, any immunosuppressive medication, peripheral arterial disease, rheumatological disease and smoking were associated with at least one outcome and had >1000 events, p-value <0.005, I <50%, 95% prediction interval excluding the null value, and absence of small-study effects in the respective meta-analysis. The risk of bias assessment using the Quality In Prognosis Studies tool indicated high risk of bias in 302 of 428 articles for study participation, 389 articles for adjustment for other prognostic factors, and 396 articles for statistical analysis and reporting.

Conclusions: Our findings could be used for prognostic model building and guide patients' selection for randomised clinical trials.
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http://dx.doi.org/10.1183/13993003.02964-2020DOI Listing
June 2021

Associations of Alcohol Consumption with Cardiovascular Disease-Related Proteomic Biomarkers: The Framingham Heart Study.

J Nutr 2021 Sep;151(9):2574-2582

Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.

Background: Alcohol consumption and cardiovascular disease (CVD) have a complex relation.

Objectives: We examined the associations between alcohol consumption, fasting plasma proteins, and CVD risk.

Methods: We performed cross-sectional association analyses of alcohol consumption with 71 CVD-related plasma proteins, and also performed prospective association analyses of alcohol consumption and protein concentrations with 3 CVD risk factors (obesity, hypertension, and diabetes) in 6745 Framingham Heart Study (FHS) participants (mean age 49 y; 53% women).

Results: A unit increase in log10 transformed alcohol consumption (g/d) was associated with an increased risk of hypertension (HR = 1.14; 95% CI: 1.04, 1.26; P = 0.007), and decreased risks of obesity (HR = 0.80; 95% CI: 0.71, 0.91; P = 4.6 × 10-4) and diabetes (HR: 0.68; 95% CI: 0.58, 0.80; P = 5.1 × 10-6) in a median of 13-y (interquartile = 7, 14) of follow-up. We identified 43 alcohol-associated proteins in a discovery sample (n = 4348, false discovery rate <0.05) and 20 of them were significant (P <0.05/43) in an independent validation sample (n = 2397). Eighteen of the 20 proteins were inversely associated with alcohol consumption. Four of the 20 proteins demonstrated 3-way associations, as expected, with alcohol consumption and CVD risk factors. For example, a greater concentration of APOA1 was associated with higher alcohol consumption (P = 1.2 × 10-65), and it was also associated with a lower risk of diabetes (P = 8.5 × 10-6). However, several others showed unexpected 3-way associations.

Conclusions: We identified 20 alcohol-associated proteins in 6745 FHS samples. These alcohol-associated proteins demonstrated complex relations with the 3 CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relation between alcohol consumption and CVD risk.
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http://dx.doi.org/10.1093/jn/nxab186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417922PMC
September 2021

Awareness, knowledge and trust in the Greek authorities towards COVID-19 pandemic: results from the Epirus Health Study cohort.

BMC Public Health 2021 06 12;21(1):1125. Epub 2021 Jun 12.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Background: To assess the level of knowledge and trust in the policy decisions taken regarding the coronavirus disease (COVID-19) pandemic among Epirus Health Study (EHS) participants.

Methods: The EHS is an ongoing and deeply-phenotyped prospective cohort study that has recruited 667 participants in northwest Greece until August 31st, 2020. Level of knowledge on coronavirus (SARS-CoV-2) transmission and COVID-19 severity was labeled as poor, moderate or good. Variables assessing knowledge and beliefs towards the pandemic were summarized overall and by sex, age group (25-39, 40-49, 50-59, ≥60 years) and period of report (before the lifting of lockdown measures in Greece: March 30th to May 3rd, and two post-lockdown time periods: May 4th to June 31st, July 1st to August 31st). A hypothesis generating exposure-wide association analysis was conducted to evaluate the associations between 153 agnostically-selected explanatory variables and participants' knowledge. Correction for multiple comparisons was applied using a false discovery rate (FDR) threshold of 5%.

Results: A total of 563 participants (49 years mean age; 60% women) had available information on the standard EHS questionnaire, the clinical and biochemical measurements, and the COVID-19-related questionnaire. Percentages of poor, moderate and good knowledge status regarding COVID-19 were 4.5, 10.0 and 85.6%, respectively. The majority of participants showed absolute or moderate trust in the Greek health authorities for the management of the epidemic (90.1%), as well as in the Greek Government (84.7%) and the official national sources of information (87.4%). Trust in the authorities was weaker in younger participants and those who joined the study after the lifting of lockdown measures (p-value≤0.001). None of the factors examined was associated with participants' level of knowledge after correction for multiple testing.

Conclusions: High level of knowledge about the COVID-19 pandemic and trust in the Greek authorities was observed, possibly due to the plethora of good quality publicly available information and the timely management of the pandemic at its early stages in Greece. Information campaigns for the COVID-19 pandemic should be encouraged even after the lifting of lockdown measures to increase public awareness.
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http://dx.doi.org/10.1186/s12889-021-11193-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196287PMC
June 2021

Alcohol consumption in the general population is associated with structural changes in multiple organ systems.

Elife 2021 06 1;10. Epub 2021 Jun 1.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Background: Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample.

Methods: We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol.

Results: We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (-1.7 × 10 ± 0.76 × 10 per doubling of alcohol consumption, p=3.0 × 10). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption.

Conclusions: Our results imply that there is not a 'safe threshold' below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.

Funding: See acknowledgements.
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http://dx.doi.org/10.7554/eLife.65325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192119PMC
June 2021

GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer.

Sci Rep 2021 May 21;11(1):10688. Epub 2021 May 21.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.

Genetic studies have examined body-shape measures adjusted for body mass index (BMI), while allometric indices are additionally adjusted for height. We performed the first genome-wide association study of A Body Shape Index (ABSI), Hip Index (HI) and the new Waist-to-Hip Index and compared these with traditional indices, using data from the UK Biobank Resource for 219,872 women and 186,825 men with white British ancestry and Bayesian linear mixed-models (BOLT-LMM). One to two thirds of the loci identified for allometric body-shape indices were novel. Most prominent was rs72959041 variant in RSPO3 gene, expressed in visceral adipose tissue and regulating adrenal cell renewal. Highly ranked were genes related to morphogenesis and organogenesis, previously additionally linked to cancer development and progression. Genetic associations were fewer in men compared to women. Prominent region-specific associations showed variants in loci VEGFA and HMGA1 for ABSI and KLF14 for HI in women, and C5orf67 and HOXC4/5 for ABSI and RSPO3, VEGFA and SLC30A10 for HI in men. Although more variants were associated with waist and hip circumference adjusted for BMI compared to ABSI and HI, associations with height had previously been reported for many of the additional variants, illustrating the importance of adjusting correctly for height.
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http://dx.doi.org/10.1038/s41598-021-89176-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139988PMC
May 2021

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Nat Commun 2021 05 10;12(1):2579. Epub 2021 May 10.

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

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-021-22338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110798PMC
May 2021

Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

Nat Genet 2021 05 6;53(5):630-637. Epub 2021 May 6.

Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
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http://dx.doi.org/10.1038/s41588-021-00835-wDOI Listing
May 2021

Tobacco Smoking and Risk for Pulmonary Fibrosis: A Prospective Cohort Study From the UK Biobank.

Chest 2021 Sep 24;160(3):983-993. Epub 2021 Apr 24.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece; Institute of Biosciences, University Research Center of Ioannina, Ioannina, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, England. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. A limited number of small studies show an effect of tobacco smoking on risk of IPF, but second-hand smoking has not been examined.

Research Question: Are smoking-related exposures associated with risk of IPF and does interaction between them exist?

Study Design And Methods: We designed a prospective cohort study using UK Biobank data, including 437,453 nonrelated men and women of White ethnic background (40-69 years of age at baseline). We assessed the effect of tobacco smoking-related exposures on risk for IPF using Cox regression adjusted for age, sex, Townsend deprivation index, and home area population density. We also examined potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to address missing data.

Results: We identified 802 incident IPF cases. We showed an association between smoking status (hazard ratio [HR], 2.12; 95% CI, 1.81-2.47), and maternal smoking (HR, 1.38; 95% CI, 1.18-1.62) with risk of IPF. In ever smokers, a dose-response relationship was observed between pack-years of smoking and risk of IPF (HR per 1-pack-year increase, 1.013; 95% CI, 1.009-1.016). Furthermore, an additive and multiplicative interaction was observed between maternal smoking and smoking status, with a relative excess risk due to interaction of 1.00 (95% CI, 0.45-1.54) and a ratio of HRs of 1.50 (95% CI, 1.05-2.14).

Interpretation: Active and maternal tobacco smoking have an independent detrimental effect on risk of IPF and work synergistically. Also, intensity of smoking presents a dose-response association with IPF, strengthening the hypothesis for a potentially causal association.
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http://dx.doi.org/10.1016/j.chest.2021.04.035DOI Listing
September 2021

Exploring pharmacogenetic variants for predicting response to anti-TNF therapy in autoimmune diseases: a meta-analysis.

Pharmacogenomics 2021 05 23;22(7):435-445. Epub 2021 Apr 23.

Department of Biology, Laboratory of Genetics, University of Patras, Patras, Greece.

The aim of this study is to explore how SNPs may affect the response to anti-TNF-α therapy in the major autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases and Spondyloarthritis. We conducted a systematic overview on the field, by assessing all studies that examined the association between polymorphisms and response to anti-TNF-α therapy in participants of European descent. In total, six independent SNPs located in , , and genes were significantly associated with response to TNF-α blockers, found mainly in disease-subgroup analyses. No common pharmacogenetic variant was identified for all autoimmune diseases under study, suggesting the requirement of more studies in the field in order to capture such predictive variants that will aid treatment selection.
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http://dx.doi.org/10.2217/pgs-2021-0019DOI Listing
May 2021

The relationship between blood pressure and risk of atrial fibrillation: a Mendelian randomization study.

Eur J Prev Cardiol 2021 Feb 9. Epub 2021 Feb 9.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

Aims: Observational studies suggest elevated blood pressure (BP) as the leading risk factor for incident atrial fibrillation (AF), but whether this relationship is causal remains unknown. In this study, we used Mendelian randomization (MR) to investigate the potential causal association of BP levels with the risk of developing AF.

Methods And Results: Genetic variants associated with the BP traits were retrieved from the International Consortium of Blood Pressure-Genome Wide Association Studies (N = 299 024). From 901 reported variants, 894 were assessed in a dedicated Genome-Wide Association Study of AF genetics, including >1 000 000 subjects of European ancestry. We used two-sample MR analyses to examine the potential causal association of systolic BP (SBP) and diastolic BP (DBP) as well as of pulse pressure (PP) with AF. MR analysis identified a potentially causal association between AF and SBP [odds ratio (OR): 1.018 per 1 mmHg increase, 95% confidence interval (CI): 1.012-1.024, P < 0.001], DBP (OR: 1.026, 95% CI: 1.016-1.035, P < 0.001), and PP (OR: 1.014, 95% CI: 1.001-1.028, P = 0.033). These findings were robust in sensitivity analyses, including the MR-Egger method and the MR pleiotropy residual sum and outlier test (MR-PRESSO). The causal relationship of BP and AF did not change when single-nucleotide polymorphisms associated with possible confounders (i.e. coronary artery disease and obesity) of the causal relationship were excluded.

Conclusions: The association between increased BP levels and the risk of AF is likely causal and applies for different BP indices. Independently from other risk factors, optimal BP control might represent an important therapeutic target for AF prevention in the general population.
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http://dx.doi.org/10.1093/eurjpc/zwab005DOI Listing
February 2021

Urate, Blood Pressure, and Cardiovascular Disease: Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials.

Hypertension 2021 02 28;77(2):383-392. Epub 2020 Dec 28.

Department of Epidemiology and Biostatistics, School of Public Health (D.G., V.K., V.Z., E.E., P.E., A.D., I.T.), Imperial College London, United Kingdom.

Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10-1.30]; =4×10), peripheral artery disease (1.12 [95% CI, 1.03-1.21]; =9×10), and stroke (1.11 [95% CI, 1.05-1.18]; =2×10). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, -2.55 mm Hg [95% CI, -4.06 to -1.05]; =1×10) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22-0.73]; =3×10) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44-1.03]; =0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803439PMC
February 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 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

Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.

BMC Med 2020 11 20;18(1):360. Epub 2020 Nov 20.

Department of Epidemiology & Biostatistics, MRC Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, W21PG, UK.

Background: Although neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis.

Methods: We searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria.

Results: A total of 204 meta-analyses from 86 studies investigating the association between either NLR or TAN and cancer outcomes met the criteria for inclusion. All but one meta-analyses found a hazard ratio (HR) which increased risk (HR > 1). We did not find sufficient meta-analyses to evaluate TAN and cancer outcomes (N = 9). When assessed for magnitude of effect, significance and bias related to heterogeneity and small study effects, 18 (9%) associations between NLR and outcomes in composite cancer endpoints (combined analysis), cancers treated with immunotherapy and some site specific cancers (urinary, nasopharyngeal, gastric, breast, endometrial, soft tissue sarcoma and hepatocellular cancers) were supported by strong evidence.

Conclusion: In total, 60 (29%) meta-analyses presented strong or highly suggestive evidence. Although the NLR and TAN hold clinical promise in their association with poor cancer prognosis, further research is required to provide robust evidence, assess causality and test clinical utility.

Trial Registration: PROSPERO CRD42017069131 .
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http://dx.doi.org/10.1186/s12916-020-01817-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678319PMC
November 2020

Early-Life Factors and Risk of Multiple Sclerosis: An MR-EWAS.

Neuroepidemiology 2020 23;54(6):433-445. Epub 2020 Oct 23.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece,

Background: Although several risk factors are associated with multiple sclerosis (MS) in adulthood, evidence for risk factors acting from birth to adolescence is scarce.

Methods: We conceived a 2-step study design, where signals from an Environment-Wide Association Study are prioritized for follow-up in a Mendelian Randomization study (MR-EWAS), to examine the association of early-life factors with risk of MS. The EWAS was conducted in UK Biobank, where we agnostically selected all the available risk factors acting from the perinatal period until the adolescence, including perinatal factors, anthropometric characteristics during childhood, male and female sexual factors, and skin phenotypic characteristics. We prioritized statistically significant risk factors to perform a 2-sample MR study using publicly available summary-level genetic data. We also calculated the power of the 2-step MR-EWAS approach under several scenarios and compared it against a 1-step hypothesis-free MR approach to detect risk factors of MS.

Results: In the EWAS, an increase per 1 year in age at menarche was associated with a lower risk of MS (OR = 0.93; 95% CI: 0.90-0.96) and a plumper than average body size at the age of 10 was associated with a higher risk of MS (OR = 1.42; 95% CI: 1.24-1.61). Individuals getting very tanned or moderately tanned were at higher risk of MS compared with individuals that never tan or get mildly to occasionally tanned (OR = 0.86; 95% CI: 0.79-0.94). The MR analysis supported the association of age at menarche and childhood body mass index (BMI) without presence of pleiotropic effects. In the multivariable MR analysis, the association of age at menarche was not statistically significant after adjusting for childhood BMI. The MR analysis for ease of tanning did not reveal a statistically significant association. In multiple scenarios, the power of MR-EWAS approach was larger than the power of a hypothesis-free MR approach.

Conclusions: We introduced the MR-EWAS, a 2-step approach that is more powerful compared with the hypothesis-free MR approach under certain scenarios, to test potential causal signals. Our comprehensive assessment of early-life risk factors of MS highlighted a potential causal role of early menarche and elevated childhood BMI for risk of MS.
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http://dx.doi.org/10.1159/000508229DOI Listing
September 2021

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Cell 2020 09;182(5):1214-1231.e11

Laboratory of Epidemiology and Population Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
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http://dx.doi.org/10.1016/j.cell.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482360PMC
September 2020

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Cell 2020 09;182(5):1198-1213.e14

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Division on Aging, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
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http://dx.doi.org/10.1016/j.cell.2020.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480402PMC
September 2020

A population-based phenome-wide association study of cardiac and aortic structure and function.

Nat Med 2020 10 24;26(10):1654-1662. Epub 2020 Aug 24.

Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, UK.

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart-brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.
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http://dx.doi.org/10.1038/s41591-020-1009-yDOI Listing
October 2020

Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.

J Neurol Neurosurg Psychiatry 2020 11 20;91(11):1201-1209. Epub 2020 Jul 20.

Department of Geriatrics, Purpan University Hospital, Toulouse, France.

Background: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention.

Methods: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised.

Results: A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B).

Interpretation: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.
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http://dx.doi.org/10.1136/jnnp-2019-321913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569385PMC
November 2020

A genome-wide scan for pleiotropy between bone mineral density and nonbone phenotypes.

Bone Res 2020 1;8:26. Epub 2020 Jul 1.

Department of Hygiene and Epidemiology, Clinical and Molecular Epidemiology Unit, School of Medicine, University of Ioannina, Ioannina, Greece.

Osteoporosis is the most common metabolic bone disorder globally and is characterized by skeletal fragility and microarchitectural deterioration. Genetic pleiotropy occurs when a single genetic element is associated with more than one phenotype. We aimed to identify pleiotropic loci associated with bone mineral density (BMD) and nonbone phenotypes in genome-wide association studies. In the discovery stage, the NHGRI-EBI Catalog was searched for genome-wide significant associations ( value < 5 × 10), excluding bone-related phenotypes. SNiPA was used to identify proxies of the significantly associated single nucleotide polymorphisms (SNPs) (  = 1). We then assessed putative genetic associations of this set of SNPs with femoral neck (FN) and lumbar spine (LS) BMD data from the GEFOS Consortium. Pleiotropic variants were claimed at a false discovery rate < 1.4 × 10 for FN-BMD and < 1.5 × 10 for LS-BMD. Replication of these genetic markers was performed among more than 400 000 UK Biobank participants of European ancestry with available genetic and heel bone ultrasound data. In the discovery stage, 72 BMD-related pleiotropic SNPs were identified, and 12 SNPs located in 11 loci on 8 chromosomes were replicated in the UK Biobank. These SNPs were associated, in addition to BMD, with 14 different phenotypes. Most pleiotropic associations were exhibited by rs479844 ( genes), which was associated with dermatological and allergic diseases, and rs4072037 ( gene), which was associated with magnesium levels and gastroenterological cancer. In conclusion, 12 BMD-related genome-wide significant SNPs showed pleiotropy with nonbone phenotypes. Pleiotropic associations can deepen the genetic understanding of bone-related diseases by identifying shared biological mechanisms with other diseases or traits.
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http://dx.doi.org/10.1038/s41413-020-0101-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329904PMC
July 2020

Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn's Disease and Ulcerative Colitis: A Mendelian Randomization Study.

Inflamm Bowel Dis 2021 01;27(2):162-168

Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC.

Methods: We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances-nicotine, alcohol, and caffeine-to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy.

Results: We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P > 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found.

Conclusions: We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.
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http://dx.doi.org/10.1093/ibd/izaa152DOI Listing
January 2021

Estimated 24-Hour Urinary Sodium Excretion and Incident Cardiovascular Disease and Mortality Among 398 628 Individuals in UK Biobank.

Hypertension 2020 09 6;76(3):683-691. Epub 2020 Jul 6.

From the Department of Epidemiology and Biostatistics, School of Public Health (P.E., D.C.M., D.S.-L., R.P., E.E., A.D., B.N., I.T.), Imperial College London, United Kingdom.

We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14302DOI Listing
September 2020

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes.

Neurology 2020 07 1;95(4):e353-e361. Epub 2020 Jul 1.

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Objective: We employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.

Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).

Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.

Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.
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http://dx.doi.org/10.1212/WNL.0000000000009814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455321PMC
July 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 Jun 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021
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