Author:
Xiu Xuehao,Zhang Haoyang,Xue Angli,Cooper David N.,Yan Li,Yang Yuedong,Yang Yuanhao,Zhao Huiying
Abstract
AbstractBackgroundObservational studies have revealed that type 2 diabetes (T2D) is associated with an increased risk of peripheral artery disease (PAD). However, whether the two diseases share a genetic basis and whether the relationship is causal remain unclear. It is also unclear as to whether these relationships differ between ethnic groups.MethodsBy leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D (European-based:Ncase= 21,926,Ncontrol= 342,747; East Asian-based:Ncase= 36,614,Ncontrol= 155,150) and PAD (European-based:Ncase= 5673,Ncontrol= 359,551; East Asian-based:Ncase= 3593,Ncontrol= 208,860), we explored the genetic correlation and putative causal relationship between T2D and PAD in both Europeans and East Asians using linkage disequilibrium score regression and seven Mendelian randomization (MR) models. We also performed multi-trait analysis of GWAS and two gene-based analyses to reveal candidate variants and risk genes involved in the shared genetic basis between T2D and PAD.ResultsWe observed a strong genetic correlation (rg) between T2D and PAD in both Europeans (rg= 0.51;p-value = 9.34 × 10−15) and East Asians (rg= 0.46;p-value = 1.67 × 10−12). The MR analyses provided consistent evidence for a causal effect of T2D on PAD in both ethnicities (odds ratio [OR] = 1.05 to 1.28 for Europeans and 1.15 to 1.27 for East Asians) but not PAD on T2D. This putative causal effect was not influenced by total cholesterol, body mass index, systolic blood pressure, or smoking initiation according to multivariable MR analysis, and the genetic overlap between T2D and PAD was further explored employing an independent European sample through polygenic risk score regression. Multi-trait analysis of GWAS revealed two novel European-specific single nucleotide polymorphisms (rs927742 and rs1734409) associated with the shared genetic basis of T2D and PAD. Gene-based analyses consistently identified one geneANKFY1and gene-gene interactions (e.g.,STARD10[European-specific] toAP3S2[East Asian-specific];KCNJ11[European-specific] toKCNQ1[East Asian-specific]) associated with the trans-ethnic genetic overlap between T2D and PAD, reflecting a common genetic basis for the co-occurrence of T2D and PAD in both Europeans and East Asians.ConclusionsOur study provides the first evidence for a genetically causal effect of T2D on PAD in both Europeans and East Asians. Several candidate variants and risk genes were identified as being associated with this genetic overlap. Our findings emphasize the importance of monitoring PAD status in T2D patients and suggest new genetic biomarkers for screening PAD risk among patients with T2D.
Funder
National Key Research and Development Program of China
Natural Science Foundation of China
Guangdong Key Field Research and Development Plan
Introducing Innovative and Entrepreneurial Teams
Guangzhou Science and Technology Research Plan
Mater Foundation
Publisher
Springer Science and Business Media LLC
Cited by
5 articles.
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