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.
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.


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.
Ng
Maggie C Y
MC
Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
Tam
Claudia H T
CH
So
Wing Yee
WY
Ho
Janice S K
JS
Chan
Alfred W
AW
Lee
Heung Man
HM
Wang
Ying
Y
Lam
Vincent K L
VK
Chan
Juliana C N
JC
Ma
Ronald C W
RC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D044466:Asian People / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002681:China; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D058851:GPI-Linked Proteins; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D019704:Protein Disulfide-Isomerases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D019208:Brain-Derived Neurotrophic Factor; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; C400427:FAIM2 protein, human; D058851:GPI-Linked Proteins; C470072:MC4R protein, human; D008565:Membrane Proteins; C485559:NEGR1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; C518910:SH2B1 protein, human; C530715:TMEM18 protein, human; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; C526504:PDIA2 protein, human; D019704:Protein Disulfide-Isomerases