The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study.
InterAct Consortium None., Scott RA., Langenberg C., Sharp SJ., Franks PW., Rolandsson O., Drogan D., van der Schouw YT., Ekelund U., Kerrison ND., Ardanaz E., Arriola L., Balkau B., Barricarte A., Barroso I., Bendinelli B., Beulens JW., Boeing H., de Lauzon-Guillain B., Deloukas P., Fagherazzi G., Gonzalez C., Griffin SJ., Groop LC., Halkjaer J., Huerta JM., Kaaks R., Khaw KT., Krogh V., Nilsson PM., Norat T., Overvad K., Panico S., Rodriguez-Suarez L., Romaguera D., Romieu I., Sacerdote C., Sánchez MJ., Spijkerman AM., Teucher B., Tjonneland A., Tumino R., van der A DL., Wark PA., McCarthy MI., Riboli E., Wareham NJ.
AIMS/HYPOTHESIS: Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association. METHODS: A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created. RESULTS: A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history. CONCLUSIONS/INTERPRETATION: Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.