A Replication Study of Genetic Variants in Genes Identified by Genome-wide Association Study in Type 2 Diabetes
Date Issued
2010
Date
2010
Author(s)
Kuo, Shan-Shan
Abstract
Background
There is a strong inheritable genetic connection in type 2 diabetes (T2D). Recently, a set of potential T2D genes in the Caucasian race have been successfully identified in several genome-wide and candidate gene association studies. In order to reduce the false-positive results of candidate genes studies and to understand the genetic variants of different races in T2D, we performed a replication study by genotyping 20 genetic variants which are in the most promising loci of Han Chinese of Taiwan to evaluate the individual and interacting effects of these variants in T2D. Based on the results, we could understand more about the roles of these candidate genes in T2D. Methods The study was comprised of 1520 type 2 diabetic cases and 1520 normoglycemic controls from Han Chinese of Taiwan. Then we performed a replication study by genotyping 20 genetic variants in the most promising loci, including ADAM30,NOTCH2,THADA,BCL11A,IGF2BP2,PPARG,ADAMTS9,WFS1,CDKAL1,VEGFA,JAZF1,SLC30A8,CDKN2A/B,HHEX,TCF7L2,EXT2,DCD,TSPAN8/LGR5,FTO and LOC387761. Allele and genotype of each SNP and their interactions were analyzed to assess the association with T2D. Results In single SNP association analysis, we replicated and confirmed 2 among the 20 genetic loci in association with T2D, with risk allele-specific odds ratios (ORs) of 1.311 (95% CI, 1.176-1.461; p<0.0045) for SLC30A8-rs13266643 and 1.238 (95% CI, 1.103-1.389; p=0.0132) for HHEX-rs1111875 after adjustment for age, gender, and body mass index, indicating that SLC30A8-rs13266643 and HHEX-rs1111875 are risk alleles of type 2 diabetes in Han Chinese in Taiwan. Besides, the result of gene-dose analysis to test cumulative effects, indicating that OR was 1.75 (95% confidence interval, 1.39 to 2.20; P<0.001) in subjects with risk alleles >42 compared with those with risk alleles <35.Gene-gene interaction analysis was carried out by means of the multifactor dimensionality reduction (MDR). This indicates that the high risk group had increased risk of T2D with OR1.584 (95%CI, 1.372-1.828), compared with the low risk group between SLC30A8 and CDKN2A . In meta-analyses, we found 8 SNPs were significantly associated with T2D in Asian and Caucasian population, and 10 SNPs showed marked heterogeneity between Asian and Caucasian populations. Conclusions We found that only two of the 20 T2D susceptibility genes identified by GWAS in Caucasian populations were confirmed to be T2D genes in our population. There is a cumulative effect of the risk alleles of these SNPs in association with T2D in Han Chinese in Taiwan. The SNP of the gene and gene-gene interaction between SLC30A8 and CDKN2A may be useful in clinical diagnosis of T2D in Taiwan.
There is a strong inheritable genetic connection in type 2 diabetes (T2D). Recently, a set of potential T2D genes in the Caucasian race have been successfully identified in several genome-wide and candidate gene association studies. In order to reduce the false-positive results of candidate genes studies and to understand the genetic variants of different races in T2D, we performed a replication study by genotyping 20 genetic variants which are in the most promising loci of Han Chinese of Taiwan to evaluate the individual and interacting effects of these variants in T2D. Based on the results, we could understand more about the roles of these candidate genes in T2D. Methods The study was comprised of 1520 type 2 diabetic cases and 1520 normoglycemic controls from Han Chinese of Taiwan. Then we performed a replication study by genotyping 20 genetic variants in the most promising loci, including ADAM30,NOTCH2,THADA,BCL11A,IGF2BP2,PPARG,ADAMTS9,WFS1,CDKAL1,VEGFA,JAZF1,SLC30A8,CDKN2A/B,HHEX,TCF7L2,EXT2,DCD,TSPAN8/LGR5,FTO and LOC387761. Allele and genotype of each SNP and their interactions were analyzed to assess the association with T2D. Results In single SNP association analysis, we replicated and confirmed 2 among the 20 genetic loci in association with T2D, with risk allele-specific odds ratios (ORs) of 1.311 (95% CI, 1.176-1.461; p<0.0045) for SLC30A8-rs13266643 and 1.238 (95% CI, 1.103-1.389; p=0.0132) for HHEX-rs1111875 after adjustment for age, gender, and body mass index, indicating that SLC30A8-rs13266643 and HHEX-rs1111875 are risk alleles of type 2 diabetes in Han Chinese in Taiwan. Besides, the result of gene-dose analysis to test cumulative effects, indicating that OR was 1.75 (95% confidence interval, 1.39 to 2.20; P<0.001) in subjects with risk alleles >42 compared with those with risk alleles <35.Gene-gene interaction analysis was carried out by means of the multifactor dimensionality reduction (MDR). This indicates that the high risk group had increased risk of T2D with OR1.584 (95%CI, 1.372-1.828), compared with the low risk group between SLC30A8 and CDKN2A . In meta-analyses, we found 8 SNPs were significantly associated with T2D in Asian and Caucasian population, and 10 SNPs showed marked heterogeneity between Asian and Caucasian populations. Conclusions We found that only two of the 20 T2D susceptibility genes identified by GWAS in Caucasian populations were confirmed to be T2D genes in our population. There is a cumulative effect of the risk alleles of these SNPs in association with T2D in Han Chinese in Taiwan. The SNP of the gene and gene-gene interaction between SLC30A8 and CDKN2A may be useful in clinical diagnosis of T2D in Taiwan.
Subjects
Type 2 diabetes (T2D)
genome-wide association studies(GWAS)
replication study
meta-analysis
heterogeneity
SDGs
Type
thesis
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