Implications of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
Diabetes (Impact Factor: 8.1). 05/2008; 57(8):2226-33. DOI: 10.2337/db07-1583
Source: PubMed


Recent genome-wide association studies have identified six novel genes for type 2 diabetes and obesity and confirmed TCF7L2 as the major type 2 diabetes gene to date in Europeans. However, the implications of these genes in Asians are unclear.
We studied 13 associated single nucleotide polymorphisms from these genes in 3,041 patients with type 2 diabetes and 3,678 control subjects of Asian ancestry from Hong Kong and Korea.
We confirmed the associations of TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, and FTO with risk for type 2 diabetes, with odds ratios ranging from 1.13 to 1.35 (1.3 x 10(-12) < P(unadjusted) < 0.016). In addition, the A allele of rs8050136 at FTO was associated with increased BMI in the control subjects (P(unadjusted) = 0.008). However, we did not observe significant association of any genetic variants with surrogate measures of insulin secretion or insulin sensitivity indexes in a subset of 2,662 control subjects. Compared with subjects carrying zero, one, or two risk alleles, each additional risk allele was associated with 17% increased risk, and there was an up to 3.3-fold increased risk for type 2 diabetes in those carrying eight or more risk alleles. Despite most of the effect sizes being similar between Asians and Europeans in the meta-analyses, the ethnic differences in risk allele frequencies in most of these genes lead to variable attributable risks in these two populations.
Our findings support the important but differential contribution of these genetic variants to type 2 diabetes and obesity in Asians compared with Europeans.

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    • "We hypothesize that obesity may modify the association between IGF2BP2 and T2DM—also called the interaction of IGF2BP2 and obesity with T2DM. Since some variants are known to affect the risk of T2DM through obesity [11,12], this work aimed to evaluate the interaction effect of IGF2BP2 and obesity on T2DM susceptibility. "
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