The determinants of the excess risk of type-2 diabetes amongst Indian Asians compared to Europeans

Abstract

Background Indian Asians are at increased risk of type-2 diabetes (T2D), insulin resistance and related metabolic disturbances compared to Europeans. The contribution of known lifestyle and genetic risk factors to the excess risk of T2D in Indian Asians is not well understood.

Methods and materials I investigated 16,774 Indian Asian and 7,301 European men and women participating in the in the London Life Sciences Population Study to determine the prevalence of T2D and related glycaemic disorders. I examined the contribution of adiposity, leisure time physical activity, major dietary macronutrients and known genetic susceptibility factors to the increased risk of T2D and related metabolic disturbances amongst Indian Asians compared to Europeans. Lastly I carried out a genome-wide association and replication study amongst 58,687 Indian Asian participants to identify novel genetic factors in this ethnic group. Results The prevalence of T2D is ~4-fold higher amongst Indian Asians than Europeans, and is not accounted for by differences in adiposity and leisure time physical activity. In dietary studies, intake of fibre is inversely related to risk of insulin resistance among Indian Asians. However, major dietary macronutrients do not account for differences in insulin resistance between Indian Asians and Europeans. In genetic studies I demonstrate association of 25 previously reported T2D genetic variants with T2D amongst Indian Asians. Of the 48 T2D genetic variants examined, risk allele frequencies were similar and effect sizes lower amongst Indian Asians compared to Europeans; therefore known T2D genetic variants do not account for the increased risk of T2D in this racial group. In the GWAS I discover 6 novel T2D genetic variants among Indian Asians (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A).

Conclusions T2D has emerged as a major healthcare problem worldwide, with rates highest among individuals of Indian Asian descent. For the first time I discover six novel genetic susceptibility factors for T2D amongst Indian Asians. However, there is a ~4-fold higher risk of T2D among Indian Asians compared to Europeans, which remains largely unexplained.