Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians.
OBJECTIVE
Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case-control studies.


METHODS
We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects.


RESULTS
We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 x 10(-3) to 4.6 x 10(-34)). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71-2.09], P = 4.6 x 10(-34)). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of beta-cell function (P = 6.9 x 10(-8) and 3 x 10(-4), respectively), which looked consistent with recessive and under-dominant models, respectively.


CONCLUSIONS
Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.
Chauhan
Ganesh
G
Functional Genomics Unit, Institute of Genomics and Integrative Biology (CSIR), Delhi, India.
Spurgeon
Charles J
CJ
Tabassum
Rubina
R
Bhaskar
Seema
S
Kulkarni
Smita R
SR
Mahajan
Anubha
A
Chavali
Sreenivas
S
Kumar
M V Kranthi
MV
Prakash
Swami
S
Dwivedi
Om Prakash
OP
Ghosh
Saurabh
S
Yajnik
Chittaranjan S
CS
Tandon
Nikhil
N
Bharadwaj
Dwaipayan
D
Chandak
Giriraj R
GR
D000368:Aged; D000369:Aged, 80 and over; D027682:Cation Transport Proteins / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D012016:Reference Values; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel
D027682:Cation Transport Proteins; D051360:Cyclin-Dependent Kinase 5; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D047495:PPAR gamma; D024661:Potassium Channels, Inwardly Rectifying; D016601:RNA-Binding Proteins; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel; C078492:HHEX protein, human; C498779:IGF2BP2 protein, human; C492522:SLC30A8 protein, human; C544894:TCF7L2 protein, human; C525110:CDKAL1 protein, human