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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our findings support the important but differential contribution of these genetic variants to type 2 diabetes and obesity in Asians compared with Europeans.
Ng
Maggie C Y
MC
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. maggieng@cuhk.edu.hk
Park
Kyong Soo
KS
Oh
Bermseok
B
Tam
Claudia H T
CH
Cho
Young Min
YM
Shin
Hyoung Doo
HD
Lam
Vincent K L
VK
Ma
Ronald C W
RC
So
Wing Yee
WY
Cho
Yoon Shin
YS
Kim
Hyung-Lae
HL
Lee
Hong Kyu
HK
Chan
Juliana C N
JC
Cho
Nam H
NH
D000328:Adult; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D007723:Korea / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases
C493966:CDKN2B protein, human; D027682:Cation Transport Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C498779:IGF2BP2 protein, human; D016601:RNA-Binding Proteins; C492522:SLC30A8 protein, human; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human