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

Abstract

Type 2 diabetes (T2D) is a critical risk factor for peripheral artery disease (PAD). However, the sex differences in genetic basis, causality, and underlying mechanisms of the two diseases are still unclear. Using sex-strati ed and ethnic-based GWAS summary, we explored the genetic correlation and causal relationship between T2D and PAD in both ethnicities and sexes by linkage disequilibrium score regression, LAVA and six Mendelian Randomization approaches. We observed stronger genetic correlations between T2D and PAD in females than males in East Asians and Europeans. East Asian females exhibit higher causal effects of T2D on PAD than males. The gene-level analysis found KCNJ11 and ANK1 genes associated with the cross-trait of T2D and PAD in both sexes. Our study provides genetic evidence for the sex difference of genetic correlations and causal relationships between PAD and T2D, indicating the importance of using sex-speci c strategies for monitoring PAD in T2D patients. BackgroundType 2 diabetes (T2D) is one of the most prevalent metabolic disorder 1 and accounts for about 90% of cases of diabetes worldwide 2 . One of the most frequent vascular complications of T2D is peripheral artery disease (PAD) 3 that is an atherosclerotic occlusive disease occurring within the peripheral limb arteries. Delayed diagnosis and inaccurate evaluation of PAD disease progression may lead to poor prognostic outcomes 4,5 . Recently, T2D has been reported as a major risk factor for PAD 6,7 . Therefore, it is urgent to elucidate the genetic mechanisms of the epidemiological association between T2D and PAD.Researchers have found that women have similar or higher PAD prevalence than men 13 , despite their lower risk of T2D [14][15][16][17] . Compared with individuals without T2D, the risk of cardiovascular mortality in women with T2D increases about threefold more than in men with T2D 18,19 . The underlying reasons are unclear. The shared genetic foundations of the links between T2D and PAD have been observed previously [8][9][10][11] . For example, CDKN2A/B was detected repeatedly in several works 8,9 . A large-scale multi-ancestry meta-analysis (N case =228,499, N contorl =1,178,783) discovered 318 novel risk loci of T2D and PAD 10 . The latest study 12 further identi ed new single nucleotide polymorphisms (SNP) associated with common genetic underpinnings of T2D and PAD in Europeans and East Asians. However, all these studies are unable to interpret the causes of these sex differences of PAD risks in women and men who are suffering from T2D.Recently, sex-strati ed genome-wide association studies (GWAS) are introduced. The method can evaluate and compare the genetic effects of SNPs between two sexes and provide evidence of sexually dimorphic associations [20][21][22][23][24][25] conducted sex-aware analyses about the genetic architecture of 530 complex traits based on 450,000 European individuals in the UK Biobank and discovered > 100 traits with at least one SNP that may account for genetic sex heterogeneity. Since sex-aware sin...