Replication and Relevance of Multiple Susceptibility Loci Discovered from Genome Wide Association Studies for Type 2 Diabetes in an Indian Population.
OBJECTIVE
Several genetic variants for type 2 diabetes (T2D) have been identified through genome wide association studies (GWAS) from Caucasian population; however replication studies were not consistent across various ethnicities. Objective of the current study is to examine the possible correlation of 9 most significant GWAS single nucleotide polymorphisms (SNPs) for T2D susceptibility as well as the interactive effect of these variants on the risk of T2D in an Indian population.


METHODS
Case-control cohorts of 1156 individuals were genotyped for 9 SNPs from an Indian population. Association analyses were performed using logistic regression after adjusting for covariates. Multifactor dimensionality reduction (MDR) analysis was adopted to determine gene-gene interactions and discriminatory power of combined SNP effect was assessed by grouping individuals based on the number of risk alleles and by calculating area under the receiver-operator characteristic curve (AUC).


RESULTS
We confirm the association of TCF7L2 (rs7903146) and SLC30A8 (rs13266634) with T2D. MDR analysis showed statistically significant interactions among four SNPs of SLC30A8 (rs13266634), IGF2BP2 (rs4402960), HHEX (rs1111875) and CDKN2A (rs10811661) genes. Cumulative analysis showed an increase in odds ratio against the baseline group of individuals carrying 5 to 6 risk alleles and discriminatory power of genetic test based on 9 variants showed higher AUC value when analyzed along with body mass index (BMI).


CONCLUSIONS
These results provide a strong evidence for independent association between T2D and SNPs for in TCF7L2 and SLC30A8. MDR analysis demonstrates that independently non-significant variants may interact with one another resulting in increased disease susceptibility in the population tested.
Department of Biotechnology, School of Life Sciences, Manipal University, Manipal-576104, Karnataka, India.
Nagaraja M
NM
Phani
Department of Medicine, Kasturba Medical College, Manipal University, Mangalore-575001, Karnataka, India.
Prabha
P
Adhikari
Department of Medicine, Kasturba Medical College, Manipal University, Manipal-576104, Karnataka, India.
Shivashankara K
SK
Nagri
Department of Medicine, Kasturba Medical College, Manipal University, Mangalore-575001, Karnataka, India.
Sydney C
SC
D'Souza
Department of Biotechnology, School of Life Sciences, Manipal University, Manipal-576104, Karnataka, India.
Kapaettu
K
Satyamoorthy
Department of Biotechnology, School of Life Sciences, Manipal University, Manipal-576104, Karnataka, India.
Padmalatha S
PS
Rai
D000328:Adult; D000368:Aged; D000483:Alleles; D015992:Body Mass Index; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007194:India; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D058011:Multifactor Dimensionality Reduction; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics; D012372:ROC Curve; D012306:Risk; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000075703:Zinc Transporter 8
C000614131:CDKN2A protein, human; D027682:Cation Transport Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C498779:IGF2BP2 protein, human; D016601:RNA-Binding Proteins; C492522:SLC30A8 protein, human; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000075703:Zinc Transporter 8