Abstract P147: Genome Wide Assessment of Shared Genetic Architecture Between Rheumatoid Arthritis and Cardiovascular Diseases Using the UK Biobank Data

Background: Patients with RA have a 2-10 folds increased risk of cardiovascular diseases (CVD) and CVD accounts for almost 50% of the excess mortality in patients with RA when compared with general population, but the mechanisms underlying such associations are largely unknown. Methods: We examined the genetic correlation, causality, and shared genetic variants between RA (Ncase=6,756, Ncontrol=452,476) and CVD (Ncase=44,246, Ncontrol=414,986) using LD Score regression (LDSC), generalized summary-data-based Mendelian Randomization (GSMR), and cross-trait meta-analysis in the UK Biobank Data. Results: In the present study, RA was significantly genetically correlated with MI, angina, CHD, and CVD after correcting for multiple testing (Rg ranges from 0.40 to 0.43, P<0.05/5). Interestingly, when stratified by frequent usage of aspirin and paracetamol, we observed increased genetic correlation between RA and CVD for participants without aspirin usage ( Rg increased to 0.54 [95%CI: 0.54, 0.78] for angina; P value=6.69х10 -6 ), and for participants with usage of paracetamol ( Rg increased to 0.75 [95%CI: 0.20, 1.29] for MI; P value=8.90х10 -3 ). Cross-trait meta-analysis identified 9 independent loci that were shared between RA and at least one of the genetically correlated CVD traits including PTPN22 at chr1p13.2 , BCL2L11 at chr2q13 , and CCR3 at chr3p21.31 ( P single trait <1х10 -3 and P meta <5х10 -8 ) highlighting potential shared etiology between them which include accelerating atherosclerosis and upregulating oxidative stress and vascular permeability. Finally, Mendelian randomization analyses observed inconsistent instrumental effects and were unable to conclude the causality and directionality between RA and CVD. Conclusion: Our results supported positive genetic correlation between RA and multiple cardiovascular traits, and frequent usage of aspirin and paracetamol may modify their associations, but instrumental analyses were unable to conclude the causality and directionality between them.

Download Full-text

Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

Download Full-text

Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study

Nutrients ◽

10.3390/nu13072218 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2218

Author(s):

Shuai Yuan ◽

Paul Carter ◽

Amy M. Mason ◽

Stephen Burgess ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

Intracerebral Hemorrhage ◽

Genetic Variants ◽

Odds Ratio ◽

Observational Studies ◽

Mendelian Randomization ◽

Coffee Consumption ◽

Uk Biobank ◽

The Uk

Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

Download Full-text

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study

PLoS Genetics ◽

10.1371/journal.pgen.1009525 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009525

Author(s):

Mark Gormley ◽

James Yarmolinsky ◽

Tom Dudding ◽

Kimberley Burrows ◽

Richard M. Martin ◽

...

Keyword(s):

Cancer Risk ◽

Genetic Variants ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Uk Biobank ◽

Limited Evidence ◽

Cholesterol Lowering ◽

Increased Risk ◽

Secondary Analyses

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

Download Full-text

Shared genetic influences on depression and menopause symptoms

Psychological Medicine ◽

10.1017/s0033291721004037 ◽

2021 ◽

pp. 1-11

Author(s):

Joeri J. Meijsen ◽

Hanyang Shen ◽

Mytilee Vemuri ◽

Natalie L. Rasgon ◽

Karestan C. Koenen ◽

...

Keyword(s):

Genetic Correlation ◽

Hot Flashes ◽

Medication Use ◽

European Ancestry ◽

Genetic Influences ◽

Uk Biobank ◽

Genetic Analyses ◽

Correlation Analyses ◽

The Uk ◽

Shared Genetic

Abstract Background Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. Methods The analysis included 232 993 women aged 39–71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. Results GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10−15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10−5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. Conclusions These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

Download Full-text

Shared genetic factors do not account for the observed co-occurrence of depression and autoimmune diseases in the UK Biobank

10.1101/2020.12.08.20242495 ◽

2020 ◽

Author(s):

Kylie P Glanville ◽

Jonathan R I Coleman ◽

Paul F O’Reilly ◽

James Galloway ◽

Cathryn M Lewis

Keyword(s):

Autoimmune Diseases ◽

Genetic Factors ◽

Disease Status ◽

Epidemiological Studies ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Increased Risk ◽

Case Status ◽

The Uk ◽

Shared Genetic

AbstractBackgroundEpidemiological studies have shown increased comorbidity between depression and autoimmune diseases. The mechanisms driving the comorbidity are poorly understood, and a highly powered investigation is needed to understand the relative importance of shared genetic influences. We investigated the evidence for pleiotropy from shared genetic risk alleles between these traits in the UK Biobank (UKB).MethodsWe defined autoimmune and depression cases using information from hospital episode statistics, self-reported conditions and medications, and mental health questionnaires. Pairwise comparisons of depression prevalence between autoimmune cases and controls, and vice-versa, were performed. Cross-trait polygenic risk score (PRS) analyses were performed to test for pleiotropy, i.e. testing whether PRS for depression could predict autoimmune disease status, and vice-versa.ResultsWe identified 28k cases of autoimmune diseases (pooling across 14 traits), and 65k cases of depression. The prevalence of depression was significantly higher in autoimmune cases compared to controls, and vice-versa. PRS for myasthenia gravis and psoriasis were significantly associated with depression case-status (p < 5.2×10−5, R2 <= 0.04%). PRS for depression were significantly associated with case-status for coeliac disease, inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis and type 1 diabetes (p < 5.8×10−5, R2 range 0.06% to 0.27%).ConclusionsConsistent with the literature, depression was more common in individuals with autoimmune diseases compared to controls, and vice-versa, in the UKB. PRS showed some evidence for involvement of shared genetic factors, but the modest R2 values suggest that shared genetic architecture accounts for only a small proportion of the increased risk across traits.

Download Full-text

Associations of sleep and circadian phenotypes with COVID-19 susceptibility and hospitalization: an observational cohort study based on the UK Biobank and a two-sample Mendelian randomization study

SLEEP ◽

10.1093/sleep/zsac003 ◽

2022 ◽

Author(s):

Zheran Liu ◽

Yaxin Luo ◽

Yonglin Su ◽

Zhigong Wei ◽

Ruidan Li ◽

...

Keyword(s):

Cohort Study ◽

Excessive Daytime Sleepiness ◽

Daytime Sleepiness ◽

Mendelian Randomization ◽

Causal Link ◽

Uk Biobank ◽

Inverse Variance ◽

Increased Risk ◽

Weighted Median ◽

The Uk

Abstract Study Objectives Sleep and circadian phenotypes are associated with several diseases. The present study aimed to investigate whether sleep and circadian phenotypes were causally linked with coronavirus disease 2019 (COVID-19)-related outcomes. Methods Habitual sleep duration, insomnia, excessive daytime sleepiness, daytime napping, and chronotype were selected as exposures. Key outcomes included positivity and hospitalization for COVID-19. In the observation cohort study, multivariable risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated. Two-sample Mendelian randomization (MR) analyses were conducted to estimate the causal effects of the significant findings in the observation analyses. Beta values and the corresponding 95% CIs were calculated and compared using the inverse variance weighting, weighted median, and MR-Egger methods. Results In the UK Biobank cohort study, both often excessive daytime sleepiness and sometimes daytime napping were associated with hospitalized COVID-19 (excessive daytime sleepiness [often vs. never]: RR=1.24, 95% CI=1.02-1.5; daytime napping [sometimes vs. never]: RR=1.12, 95% CI=1.02-1.22). In addition, sometimes daytime napping was also associated with an increased risk of COVID-19 susceptibility (sometimes vs. never: RR= 1.04, 95% CI=1.01-1.28). In the MR analyses, excessive daytime sleepiness was found to increase the risk of hospitalized COVID-19 (MR IVW method: OR = 4.53, 95% CI = 1.04-19.82), whereas little evidence supported a causal link between daytime napping and COVID-19 outcomes. Conclusions Observational and genetic evidence supports a potential causal link between excessive daytime sleepiness and an increased risk of COVID-19 hospitalization, suggesting that interventions targeting excessive daytime sleepiness symptoms might decrease severe COVID-19 rate.

Download Full-text

Effect of n-3 polyunsaturated fatty acids on ischemic heart disease and cardiometabolic risk factors: a two-sample Mendelian randomization study

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02342-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bayi Xu ◽

Zhixia Xu ◽

Duanmin Xu ◽

Xuerui Tan

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Blood Pressure ◽

Fatty Acids ◽

Cardiometabolic Risk ◽

Mendelian Randomization ◽

Meta Analysis ◽

Cardiometabolic Risk Factors ◽

Uk Biobank ◽

The Uk

Abstract Background The cardioprotective ability of n-3 polyunsaturated fatty acids (PUFAs) is controversial. Most studies suggest a specific role for PUFAs in cardioprotection from ischemic heart disease (IHD). However, few studies have used genetic biomarkers of n-3 PUFAs to examine their potential relationships with IHD. This study aimed to use Mendelian randomization to evaluate whether genetically-predicted n-3 PUFAs affect IHD and cardiometabolic risk factors (CRFs). Methods Genetic variants strongly (p < 5 × 10–8) and independently (r2 > 0.1) associated with n-3 PUFAs were derived from the CHARGE Consortium (including 8,866 subjects of European ancestry) and were used as instrumental variables (IVs) for evaluating the effect of n-3 PUFAs, including α-linolenic acid (ALA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Data on the associations between the IVs and IHD, myocardial infarction, and CRFs (including diabetes, lipids, blood pressure, body mass index, and waist-to-hip ratio (WHR)) were obtained from the UK Biobank SOFT CAD GWAS with the CARDIoGRAMplusC4D 1000 Genomes-based GWAS (113,937 IHD cases and 339,115 controls), the Myocardial Infarction Genetics and CARDIoGRAM Exome consortia (42,335 MI cases and 78,240 controls), the DIAbetes Genetics Replication And Meta-analysis consortium (26,676 diabetes mellitus cases and 132,532 controls), the Global Lipids Genetics Consortium (n = 196,475), the International Consortium for Blood Pressure (n = 69,395), and the meta-analysis of GWAS for body fat distribution in the UK Biobank and Genetic Investigation of Anthropometric Traits (n = 694,649). Results Genetically-predicted higher ALA was associated with lower risk of IHD, type 2 diabetes (T2D), and lower serum lipids. The effect size per 0.05-unit increase (about 1 standard deviation) in plasma ALA level) was − 1.173 (95% confidence interval − 2.214 to − 0.133) for IHD. DPA and EPA had no association with IHD but were associated with a higher risk of T2D, higher levels of lipids or WHR. DHA had no association with IHD or CRFs. Conclusions Our study suggests a benefit of ALA for IHD and its main risk factors. DHA, DPA, and EPA had no association with IHD but were partly associated with increasing cardiometabolic risk factors.

Download Full-text

Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study

European Journal of Epidemiology ◽

10.1007/s10654-021-00737-5 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Amy M. Mason ◽

Stephen Burgess ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Diseases ◽

Association Studies ◽

European Ancestry ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genetic Liability ◽

Genome Wide ◽

Increased Risk ◽

The Uk

AbstractThe present study aimed to determine the associations between insomnia and cardiovascular diseases (CVDs) using Mendelian randomisation (MR) analysis. As instrumental variables, we used 208 independent single-nucleotide polymorphisms associated with insomnia at the genome-wide significance threshold in a meta-analysis of genome-wide association studies in the UK Biobank and 23andMe including a total of 397 959 self-reported insomnia cases and 933 057 non-cases. Summary-level data for nine CVDs were obtained from the UK Biobank including 367 586 individuals of European ancestry. After correction for multiple testing, genetic liability to insomnia was associated with higher odds of six CVDs, including peripheral arterial disease (odd ratio (OR) 1.22; 95% confidence interval (CI), 1.21, 1.33), heart failure (OR 1.21; 95% CI, 1.13, 1.30), coronary artery disease (OR 1.19; 95% CI, 1.14, 1.25), ischaemic stroke (OR 1.15; 95% CI, 1.06, 1.25), venous thromboembolism (OR 1.13; 95% CI, 1.07, 1.19) and atrial fibrillation (OR 1.10; 95% CI, 1.05, 1.15). There were suggestive associations for aortic valve stenosis (OR, 1.17; 95% CI, 1.04, 1.32) and haemorrhagic stroke (OR 1.14; 95% CI, 1.00, 1.29) but no association for abdominal aortic aneurysm (OR, 1.14, 95% CI, 0.98, 1.33). The patterns of associations remained with mild attenuation in multivariable MR analyses adjusting for genetically correlated phenotypes and potential mediators, including sleep duration, depression, body mass index, type 2 diabetes and smoking. The present MR study suggests potential causal associations of genetic liability to insomnia with increased risk of a broad range of CVDs.

Download Full-text

Genetically determined risk of keratinocyte carcinoma and risk of other cancers

International Journal of Epidemiology ◽

10.1093/ije/dyaa265 ◽

2020 ◽

Author(s):

Jean Claude Dusingize ◽

Catherine M Olsen ◽

Jiyuan An ◽

Nirmala Pandeya ◽

Upekha E Liyanage ◽

...

Keyword(s):

Genetic Variants ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Epidemiological Studies ◽

Risk Scores ◽

Cancer Site ◽

Uk Biobank ◽

Individual Level ◽

Increased Risk ◽

The Uk

Abstract Background Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. Methods In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. Results Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13–1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03–1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. Conclusion Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.

Download Full-text

Association of genetically predicted serum estradiol with risk of thromboembolism in men: A mendelian randomization study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab164 ◽

2021 ◽

Author(s):

Maria Nethander ◽

Johan Quester ◽

Liesbeth Vandenput ◽

Claes Ohlsson

Keyword(s):

Ischemic Stroke ◽

Odds Ratio ◽

Mendelian Randomization ◽

Causal Role ◽

Gene Region ◽

Uk Biobank ◽

Increased Risk ◽

Self Reports ◽

The Uk

Abstract Context An association was recently reported between genetic markers related to high testosterone and increased risk of thromboembolism in men but a possible causal role of estradiol for risk of thromboembolism in men remains unknown. Objective To determine whether endogenous estradiol has a causal role in thromboembolism in men. Design Two-sample mendelian randomization study using gene-based genetic instruments Setting UK Biobank Participants We assessed the association between endogenous estradiol genetically predicted by 22 variants in the CYP19A1 gene region and risk of thromboembolism (5815 cases) in 170,593 unrelated men of white ancestry in the UK Biobank. Main Outcome Measure Thromboembolism based on self-reports, hospital episodes, and death. Results Endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with risk of thromboembolism (odds ratio per SD increase in estradiol 0.74, 95% confidence interval 0.62-0.90). In contrast, genetic variants in the JMJD1C gene, used as a predictor of high endogenous testosterone, were associated with an increased risk of thromboembolism (odds ratio per SD increase in testosterone 1.39, 1.12-1.72). Subsequent explorative analyses evaluating potential repercussions of thromboembolism revealed that endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with risk of ischemic stroke (0.68, 0.49-0.95) but not myocardial infarction (0.97, 0.84-1.13). Conclusions Genetically predicted estradiol was inversely associated with risk of thromboembolism and ischemic stroke in men. The ratio between testosterone and estradiol, determined by aromatase (CYP19A1) activity, may contribute to the overall impact of sex steroids on thromboembolism in men.

Download Full-text