Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation

Sha Lin; Jie Tang; Xing Li; Gang Wu; Yi-Fei Lin; Yi-Fei Li

doi:10.12998/wjcc.v11.i36.8475

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation

World J Clin Cases. 2023 Dec 26;11(36):8475-8485. doi: 10.12998/wjcc.v11.i36.8475.

Authors

Sha Lin¹, Jie Tang¹, Xing Li¹, Gang Wu¹, Yi-Fei Lin², Yi-Fei Li^{1

3}

Affiliations

¹ Department of Pediatrics and Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
² Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
³ Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China. liyfwcsh@scu.edu.cn.

Abstract

Background: Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated.

Aim: In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF.

Methods: MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used.

Results: In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031).

Conclusion: The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.

Keywords: Atrial fibrillation; Genome-wide association study; Insulin-like growth factor binding protein 3; Insulin-like growth factor family; Mendelian randomization.