Does genetic heterogeneity account for the divergent risk of type 2 diabetes in South Asian and white European populations?

Abstract

Aims/hypothesis: South Asians are up to four times more likely to develop type 2 diabetes than white Europeans. It is postulated that the higher prevalence results from greater genetic risk. To evaluate this hypothesis, we: (1) systematically reviewed the literature for single nucleotide polymorphisms (SNPs) predisposing to type 2 diabetes in South Asians; (2) compared risk estimates, risk alleles and risk allele frequencies of predisposing SNPs between South Asians and white Europeans; and (3) tested the association of novel SNPs discovered from South Asians in white Europeans.

Methods: MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane registry were searched for studies of genetic variants associated with type 2 diabetes in South Asians. Meta-analysis estimates for common and novel bi-allelic SNPs in South Asians were compared with white Europeans from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. The population burden from predisposing SNPs was assessed using a genotype score.

Results: Twenty-four SNPs from 21 loci were associated with type 2 diabetes in South Asians after meta-analysis. The majority of SNPs increase odds of the disorder by 15-35% per risk allele. No substantial differences appear to exist in risk estimates between South Asians and white Europeans from SNPs common to both groups, and the population burden also does not differ. Eight of the 24 are novel SNPs discovered from South Asian genome-wide association studies, some of which show nominal associations with type 2 diabetes in white Europeans.

Conclusions/interpretation: Based on current literature there is no strong evidence to indicate that South Asians possess a greater genetic risk of type 2 diabetes than white Europeans.

Fig. 1

(a) Overview of the study design. (b) Flow diagram of the systematic review of South Asian literature investigating genetic variants predisposing to type 2 diabetes (first objective of study). T2DM, type 2 diabetes mellitus

Fig. 2

Forest plot of SNPs associated with type 2 diabetes in South Asians and comparison with white Europeans from DIAGRAM. Chr, chromosome; het, heterogeneity; no., number; SA, South Asian; WC, white European

Fig. 3

Venn diagram of SNPs common to South Asians and white Europeans and SNPs unique to both groups. CENTD2 is also known as ARAP1. The green box includes genes with GWAS evidence for association with type 2 diabetes; the pink box includes genes with GWAS evidence in white Europeans and association with type 2 diabetes in this meta-analysis; and yellow with genes identified from a trans-ethnic meta-analysis of South Asians and white Europeans [49]

Fig. 4

Gene score of SNPs in South Asians and white Europeans. The gene score was constructed using effect estimates and RAFs from SNPs common to both groups