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A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity.

ABSTRACT: Growing evidence suggests that inflammation is a significant contributor to different cardiovascular diseases (CVDs). Mendelian randomization (MR) was performed to assess the causal inference between plasma soluble IL6 receptor (sIL6R), a negative regulator of IL6 signaling, and different cardiovascular and immune-related disorders. Cis-MR with multiple instrumental variables showed an inverse association of sIL6R with rheumatoid arthritis, atrial fibrillation, stroke, coronary artery disease, and abdominal aortic aneurysm. However, genetically-determined sIL6R level was positively associated with atopic dermatitis and asthma. Also, sIL6R level was associated with longevity, as evaluated by parental age at death, a heritable trait. Gene-based association analysis with S-PrediXcan by using tissues from GTExV7 showed that IL6R tissue expression-disease pair associations were consistent with the directional effect of IL6 signaling identified in MR. Genetically-determined reduced IL6 signaling lowers the risk of multiple CVDs and is associated with increased longevity, but at the expense of higher atopic risk.

SUBMITTER: Rosa M

PROVIDER: S-EPMC6754413 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity.

Rosa Mickael M Chignon Arnaud A Li Zhonglin Z Boulanger Marie-Chloé MC Arsenault Benoit J BJ Bossé Yohan Y Thériault Sébastien S Mathieu Patrick P

NPJ genomic medicine 20190920

Growing evidence suggests that inflammation is a significant contributor to different cardiovascular diseases (CVDs). Mendelian randomization (MR) was performed to assess the causal inference between plasma soluble IL6 receptor (sIL6R), a negative regulator of IL6 signaling, and different cardiovascular and immune-related disorders. <i>Cis</i>-MR with multiple instrumental variables showed an inverse association of sIL6R with rheumatoid arthritis, atrial fibrillation, stroke, coronary artery dis ...[more]

PMID: 31552141

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Project description:ImportanceSmoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood.ObjectiveTo determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke.Design, setting, and participantsMendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462?690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60?801 cases, 123?504 controls), PAD (VA Million Veteran Program; up to 24?009 cases, 150?983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406?111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020.ExposuresGenetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index).Main outcomes and measuresRisk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke.ResultsGenetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56; P?=?3.6?×?10-16), CAD (OR, 1.48; 95% CI, 1.25-1.75; P?=?4.4?×?10-6), and stroke (OR, 1.40; 95% CI, 1.02-1.92; P?=?.04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19; P?=?.02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84; P?=?.004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors.Conclusions and relevanceIn this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.

Project description:BACKGROUNDS:Elucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures. METHODS:We conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in the survival context. RESULTS:Our results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e-04), heart failure (p=9.03e-03), and cardiovascular diseases (CVD) (p=1.69e-03) and the causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e-03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e-02). In addition, LDL-C and triglycerides are inversely associated with the risks of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326. CONCLUSIONS:Our results highlight the involvement of BMI in the development of multiple age-related diseases. Some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these diseases.

Dataset Information

A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity.

Publications

A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity.

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