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. 2011 Apr;54(4):776-82.
doi: 10.1007/s00125-011-2044-5. Epub 2011 Jan 26.

Genetic predisposition to obesity leads to increased risk of type 2 diabetes

S Li  1 , J H Zhao, J Luan, C Langenberg, R N Luben, K T Khaw, N J Wareham, R J F Loos
Affiliations

Genetic predisposition to obesity leads to increased risk of type 2 diabetes

S Li et al. Diabetologia. 2011 Apr.

Abstract

Aims/hypothesis: Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort.

Methods: We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39-79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models.

Results: Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005-1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967-1.039; p = 0.89).

Conclusions/interpretation: The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect.

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Figures

Fig. 1
Fig. 1
Illustration of the triangular relationship among the genetic predisposition score, BMI, and type 2 diabetes. βGB represents the effect size of the score on BMI, βBD the effect size of BMI on the risk of developing type 2 diabetes (lnOR), βO the observed effect size of the score on type 2 diabetes, and βE the expected effect size of the score on type 2 diabetes based on βGB and βBD. βE and βO were compared by Student’s t test. Numbers in parentheses are 95% CIs
See this image and copyright information in PMC

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