Genetics of height and risk of atrial fibrillation: A Mendelian randomization study

Levin, Michael G.; Judy, Renae; Gill, Dipender; Vujkovic, Marijana; Verma, Shefali S.; Bradford, Yuki; Ritchie, Marylyn D.; Hyman, Matthew C.; Nazarian, Saman; Rader, Daniel J.; Voight, Benjamin F.; Damrauer, Scott M.

doi:10.1371/journal.pmed.1003288

Cited by 91 publications

(59 citation statements)

References 43 publications

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“…39 Whilst the reason underpinning these changes is unclear, a recent Mendelian randomization study suggested taller people had higher risk of atrial fibrillation and hence failure to take into account height in the analyses may have led to the positive observed association in the main analyses given some of the lung function instruments were also related to height. 40 This may also explain the null findings upon adjustment for height in the multivariable Mendelian randomization.…”

Section: Discussionmentioning

confidence: 97%

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study

Yeung

Borges

Lawlor

et al. 2021

Thorax

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IntroductionObservational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be confounded. We conducted a two sample Mendelian randomisation study using summary statistics from genome-wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.MethodsWe obtained genetic instruments for forced expiratory volume in 1 s (FEV1: 260) and forced vital capacity (FVC: 320) from publicly available UK Biobank summary statistics (n=421 986) and applied to GWAS summary statistics for coronary artery disease (CAD) (n=184 305), stroke (n=446 696), atrial fibrillation (n=1 030 836) and heart failure (n=977 320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes, with various sensitivity analyses. Bidirectional Mendelian randomisation was used to assess reverse causation.ResultsFEV1 and FVC were inversely associated with CAD (OR per SD increase, 0.72 (95% CI 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (95% CI 0.82 to 1.00)) and some stroke subtypes. FEV1 and FVC were inversely associated with type 2 diabetes and systolic blood pressure. Sensitivity analyses produced similar findings although the association with CAD was attenuated after adjusting for height (eg, OR for 1SD FEV10.95 (0.75 to 1.19), but not for stroke or type 2 diabetes. There was no strong evidence for reverse causation.ConclusionHigher lung function likely protect against CAD and stroke.

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Section: Discussionmentioning

confidence: 97%

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study

Yeung

Borges

Lawlor

et al. 2021

Thorax

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“…Moreover, consistent results were obtained in the recurring MR analyses. Another MR study ( 44 ) found that taller people had higher risk of AF and considering part instruments of the lung function were also related to height, which may account for the invalid results of height adjustment in GWAS summary data. Furthermore, the positive relation of FEV1/FVC with AF in our uvMR Egger analysis is somewhat unexpected although the association disappeared after adjusting for FEV1 and FVC in mvMR method.…”

Section: Discussionmentioning

confidence: 99%

Causal Relationship Between Lung Function and Atrial Fibrillation: A Two Sample Univariable and Multivariable, Bidirectional Mendelian Randomization Study

Zhang

et al. 2021

Front. Cardiovasc. Med.

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Background: Observational studies have identified impaired lung function accessed by forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or the ratio of FEV1 over FVC (FEV1/FVC) as an independent risk factor for atrial fibrillation (AF). However, the result may be affected by confounders or reverse causality.Methods: We performed univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR to jointly estimate the causality of lung function with AF. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, three complementary sensitive analyses approaches including MR-Egger regression, weighted median (WM) MR and Pleiotropy Residual Sum and Outlier (MR-PRESSO) in uvMR as well as mvMR-Egger and mvMR-PRESSO in mvMR were applied to control for pleiotropy. Linkage disequilibrium score (LDSC) regression was applied to estimate genetic correlation between lung function and AF.Results: All forward and reverse uvMR analyses consistently suggested absent causal relations between lung function and AF risk [forward IVW: odds ratio (OR)FEV1 = 1.031, 95% CI = 0.909–1.169, P = 0.630; ORFVC = 1.002, 95% CI = 0.834–1.204, P = 0.982; ORFEV1/FVC = 1.076, 95% CI = 0.966–1.199, P = 0.182; reverse IVW: ORFEV1 = 0.986, 95% CI = 0.966–1.007, P = 0.187; ORFVC = 0.985, 95% CI = 0.965–1.006, P = 0.158; ORFEV1/FVC = 0.994, 95% CI = 0.973–1.015, P = 0.545]. The forward MR-Egger showed that each standard deviation (SD) increase in FEV1/FVC was related to a higher AF risk (OR = 1.502, 95% CI = 1.178–1.915, P = 0.006) without heterogeneity (Q_pval = 0.064), but pleiotropy effect exist (intercept = −0.017, P = 0.012). However, this significant effect disappeared after adjustment of FEV1 and FVC (OR = 1.523, 95% CI = 0.445–5.217, P = 0.503) in mvMR. No evidence was found for independent causal effects of FEV1 and FVC on AF in mvMR analysis by using mvIVW method (ORFEV1 = 0.501, 95% CI = 0.056–4.457, P = 0.496; ORFVC = 1.969, 95% CI = 0.288–13.474, P = 0.490). Notably, the association between lung function and AF were replicated using the FinnGen cohort data.Conclusions: Our findings reported no coheritability between lung function and AF, and failed to find substantial causal relation between decreased lung function and risk of AF. However, lung function and AF were both associated with inflammation, which may be potential pathway, warranting further study.

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“…Single-nucleotide polymorphisms that reached genome-wide significance ( p < 5 * 10 −8 ) were selected as instrumental variables. These SNPs were further linkage disequilibrium (LD)-pruned (distance threshold = 10,000 kb, r 2 < 0.001) to ensure independence among the genetic variants ( 28 ). If the selected SNPs were not collected in the GWAS of HF, proxy SNPs in the linkage disequilibrium ( r 2 > 0.8) were chosen for substitution.…”

Section: Methodsmentioning

confidence: 99%

Genetically Determined Inflammatory Biomarkers and the Risk of Heart Failure: A Mendelian Randomization Study

Peng

Guan

et al. 2021

Front. Cardiovasc. Med.

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Background: Positive associations between inflammatory biomarkers and the risk of heart failure (HF) have been reported in conventional observational studies. However, the causal effects of inflammatory biomarkers on HF have not been fully elucidated. We conducted a Mendelian randomization (MR) study to examine the possible etiological roles of inflammatory biomarkers in HF.Methods: Summary statistical data for the associations between single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP), fibrinogen, and components of the interleukin-1 (IL-1)-interleukin-6 (IL-6) inflammatory signaling pathway, namely, interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r), were obtained from genome-wide association studies (GWASs) for individuals of European descent. The GWAS dataset of 977,323 participants of European ancestry, which included 47,309 HF cases and 930,014 controls, was collected to identify genetic variants underlying HF. A two-sample Mendelian randomization framework was implemented to examine the causality of the association between these inflammatory biomarkers and HF.Results: Our MR analyses found that genetically determined CRP and fibrinogen were not causally associated with HF risk (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.84–1.02, p = 0.15; OR = 0.94, 95% CI = 0.55–1.58, p = 0.80, respectively). These findings remained consistent using different Mendelian randomization methods and in sensitivity analyses. For the IL-1-IL-6 pathway, causal estimates for IL-6 (OR = 0.86, 95% CI 0.81–0.91, p < 0.001), but not for IL-1β, IL-1ra, or sIL-6r, were significant. However, the association between genetically determined IL-6 and HF risk became non-significant after excluding SNPs with potential pleiotropy (OR = 0.89, 95% CI = 0.77–1.03, p = 0.12).Conclusion: Our study did not identify convincing evidence to support that CRP and fibrinogen, together with their upstream IL-1-IL-6 signaling pathway, were causally associated with HF risk.

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Genetics of height and risk of atrial fibrillation: A Mendelian randomization study

Cited by 91 publications

References 43 publications

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study

Causal Relationship Between Lung Function and Atrial Fibrillation: A Two Sample Univariable and Multivariable, Bidirectional Mendelian Randomization Study

Genetically Determined Inflammatory Biomarkers and the Risk of Heart Failure: A Mendelian Randomization Study

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