Genetic evidence for a causal relationship between type 2 diabetes and peripheral artery disease in both Europeans and East Asians

Abstract

Background Observational 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. Methods By 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. Results We 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 gene ANKFY1 and gene-gene interactions (e.g., STARD10 [European-specific] to AP3S2 [East Asian-specific]; KCNJ11 [European-specific] to KCNQ1 [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. Conclusions Our 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.

Sex differences of the shared genetic landscapes between type 2 diabetes and peripheral artery disease in East Asians and Europeans

“…Observational studies identi ed signi cant phenotypic correlations between T2D and PAD 33,34 , and indicated patients suffering from T2D with higher risks to developing into PAD. A subsequent study further investigated the shared genetic architecture between T2D and PAD in Europeans and East Asians 12 . Previous work has opened avenues to better understand the genetic heterogeneity underlying T2D and PAD.…”

Advancing a causal role of type 2 diabetes and its components in developing macro‐ and microvascular complications via genetic studies

“…Systolic blood pressure had strong causal effect among Europeans but showed no evidence among East Asian population, which could indicate an ancestry‐based role for systolic blood pressure in the development of chronic kidney disease. Another Mendelian randomization study by Xuehao et al 52 found consistent causal effect of type 2 diabetes on higher risk of peripheral artery disease among both European and East Asian individuals. Such evidence could suggest that type 2 diabetes is less likely to be affected by ethnic variation in the development of vascular complications, however, multiple studies among different ethnic groups are needed for better judgement and understanding.…”

TEMR: Trans-ethnic Mendelian Randomization Method using Large-scale GWAS Summary Datasets

“…A number of trans-ethnic MR analyses has been published, predominantly featured in applied research articles [26][27][28] . The common approach in these studies involves conducting separate MR analyses within distinct ethnic groups and subsequently comparing the nuances in the MR results between these groups.…”