Abstract MP031: Birth Weight, Genetic-Susceptibility and Adulthood Risk of Type 2 Diabetes

Background: Both stressful intrauterine milieus and genetic susceptibility have been linked to later life diabetes risk. The present study aims to examine the interaction between low birth weight, a surrogate measure of stressful intrauterine milieus, and genetic susceptibility in relation to risk of type 2 diabetes in adulthood. Methods: The analysis included two independent, nested case-control studies of in total 2591 cases of type 2 diabetes and 3052 healthy controls from prospective cohorts: the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We developed 2 genotype scores using susceptibility loci recently identified through Genome Wide Association Studies: 1) an ‘obesity genotype score’ based on 32 BMI-predisposing single nucleotide polymorphisms (SNPs); and 2) a ‘diabetes genotype score’ based on 35 diabetes-predisposing SNPs. Results: Both the obesity genotype score and diabetes genotype score showed consistently significant association with risk of type 2 diabetes in NHS and HPFS ( P for trend < 0.01). In the pooled sample of the two cohorts, we found significant interaction between birth weight and obesity genotype score in relation to type 2 diabetes ( P for interaction=0.017). In low birth weight individuals (≤ 2.5 kg), the multivariable-adjusted odds ratio (OR) was 2.55 (95% confidence interval [CI]: 1.34–4.84) in the comparison of the highest with the lowest quartile of the obesity genotype score, while the OR was 1.27 (95%CI: 1.04–1.55) among individuals with birth weight above 2.5kg. Diabetes genotype score also showed stronger association with type 2 diabetes risk in individuals with low birth weight than those with high birth weight. Comparing individuals of the highest with the lowest quartile of the diabetes genotype score, the multivariable-adjusted odds ratio was 3.80 (95%CI: 1.76–8.24) among individuals with low birth weight and was 2.27 (95%CI: 1.82–2.83) among those with high birth weight. However, test for interaction was marginal ( P =0.16). Conclusion: Our data suggest low birth weight and genetic susceptibility to obesity may synergistically affect adulthood risk of type 2 diabetes.