Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese

J Clin Endocrinol Metab. 2010 May;95(5):2418-25. doi: 10.1210/jc.2009-2077. Epub 2010 Mar 9.

Abstract

Objective: Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity and type 2 diabetes (T2D) in Chinese.

Research design and methods: We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong.

Results: The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 x 10(-8) < P < 0.024), and/or obesity risk (odds ratio 1.14-1.22, 2.0 x 10(-5) < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09-1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m(2) in BMI with each additional copy of at-risk allele (P(trend) = 4.2 x 10(-12)).

Conclusions: Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Apoptosis Regulatory Proteins / genetics
  • Asian Continental Ancestry Group / genetics
  • Brain-Derived Neurotrophic Factor / genetics
  • Cell Adhesion Molecules, Neuronal / genetics
  • China
  • DNA-Binding Proteins / genetics
  • Diabetes Mellitus, Type 2 / genetics*
  • GPI-Linked Proteins
  • Genetic Variation*
  • Humans
  • Membrane Proteins / genetics
  • Obesity / genetics*
  • Potassium Channels, Voltage-Gated / genetics
  • Protein Disulfide-Isomerases / genetics
  • Proteins / genetics
  • Receptor, Melanocortin, Type 4 / genetics
  • Transcription Factors / genetics
  • Vesicular Transport Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Brain-Derived Neurotrophic Factor
  • Cell Adhesion Molecules, Neuronal
  • DNA-Binding Proteins
  • ETV5 protein, human
  • FAIM2 protein, human
  • GPI-Linked Proteins
  • MC4R protein, human
  • Membrane Proteins
  • NEGR1 protein, human
  • Potassium Channels, Voltage-Gated
  • Proteins
  • Receptor, Melanocortin, Type 4
  • SH2B1 protein, human
  • TMEM18 protein, human
  • Transcription Factors
  • Vesicular Transport Proteins
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • PDIA2 protein, human
  • Protein Disulfide-Isomerases