The Chinese population accounts for approximately 20 percent of the world's population. The replication study of T2D genes/loci in this population has expanded the genetic investigation of T2D in a large ethnic group. Previous association studies of genetic variants in the eight genes and T2D of the Han Chinese populations were from Hong Kong (south), east and north China. The Chinese population of this study was taken from a Han Chinese population in western part of China. Because significant differences exist among Han Chinese subpopulations in China [32, 33], the population in this study represented a different type of Han Chinese subpopulalation for T2D association study of genetics, which was also supported by the allele frequency differences of SNPs in the significantly associated T2D genes among Han Chinese subpopulations from different parts of China, for instance, the C allele frequency of rs1326634 in SCL30A8 gene was 0.59 in cases and 0.54 in controls in this study compared to 0.42 in cases and 0.47 in controls in the study by Xiang et al. . Therefore, this study not only replicated, but also complemented the previous studies of genetic variants and T2D in the Chinese population.
Although rs7903146 in TCF7L2 was confirmed as the strongest T2D genetic variant in European original populations , the association of rs7903146 with T2D in east Asian populations, especially in China, remains unclear due to the low frequency of the risk allele of rs7903146 (<5%). Miyake et al. demonstrated that SNP rs7903146 in the TCF7L2 gene was significantly associated with T2D in the Japanese population; the adjusted p value was 0.0011 in a study composed of 1,921 cases and 1,696 controls . In another study dealing with the Japanese population, there was a marginal association between rs7903146 and T2D. The p value was 0.0485 in a cohort composed of 1,630 cases and 1,064 controls . Although Chang, et al. did not find a signifcant association between rs7903146 and T2D in Taiwan Han Chinese populaiton study that included a p value of 0.36 (a study of 760 cases and 760 controls) , Maggie, et al. showed that rs7903146 was significantly associated with T2D in a Hong Kong Chinese population; the p value was 0.038 with 433 cases and 419 controls . Ren, et al. also indicated that a trend association between rs7903146 and T2D with a p value of 0.063 in a study of 481 cases and 491 controls . Our results further demonstrated that rs7903146 in the TCF7L2 gene was significantly associated with T2D in the Han Chinese population in mainland China; the T risk allele of rs7903146 conferred a 1.58 fold increasing the likelihood of having T2D, as compared with individuals who do not carry any of the four risk alleles (adjusted p = 1.0 × 10-3, dominant model). This results was also supported by the meta- analysis of the association between rs7903146 in TCF7L2 gene and T2D in the four Han Chinese population(Table 2) and in the East Asian populations . Given the factor of low MAF (minor allele frequency) of rs7903146 (<5%), and the 5.5% T2D prevalence in adults in China , a power calculation using an additive genetic model showed that approximately 1,500 cases and 1,500 controls would be necessary to achieve 80% power for rs7903146. This indicated that the sample size in some of the previous studies was underpowered in evaluating the association of rs7903146 and T2D in the Chinese populations [24, 25, 27]. Nevertheless, all studies redarding the association of TCF7L2 and T2D in Chinese populations indicated that other different genetic variants in the TCF7L2 gene showed a significant association with T2D in Chinese populations [20, 24–26]. We also confirmed that another SNP rs6585205 in TCF7L2 gene was significantly associated with T2D in the studied cohort with an odd ratio of 1.31 (adjust p = 4.0 × 10-4, dominant model). Although it is certain that TCF7L2 plays an important role in the development of T2D in east Asian populations, it appears that the contribution of TCF7L12 to T2D development in east Asian populations is not as strong as that in Caucasian populations.
Consistent with previous findings [20, 21, 23, 35], we also confirmed that SNPs in the CDKAL1, HHEX, and SLC30A8 genes showed a significant association with T2D in the Han Chinese population being studied. In this study, we found a significant association between all three SNPs typed, including rs1111875, rs7923837 and rs5015480, in the IDE - KIF11 - HHEX region, and T2D in the Chinese population. Among the three SNPs in this region, rs7923837 showed the most significant association with T2D with an odds ratio of 1.39 (adjusted p = 8.62 × 10-6, dominant model). The association is similar to that previously reported in Chinese populations , which further confirmed that the variants in this region play an important role in T2D for different races. However, the frequencies of risk alleles in the three SNPs were much lower in east Asian populations including China and Japan, than those reported in European original populations.
Among the four T2D associated genes, SNPs in CDKAL1 and SLC30A8 showed the most significant association with T2D in this study, and the significant association between the SNPs of both genes and T2D was observed all three models (multiplicative, dominant and recessive models) being tested. Only one SNP rs10946398 among the three SNPs we typed in CDKAL1 showed a significant association with T2D in this study, however this SNP showed to have the most significant association with T2D in all three models (multiplicative, dominant and recessive models) being tested among all nineteen SNPs we typed, indicating that the CDKAL1 gene may contribute more than the other three T2D-related genes in the development of T2D in Chinese patients being studied. All three SNPs, including rs13266634, rs3802177 and rs11558471 in the SLC30A8 gene were strongly associated with T2D in this study; however, rs3802177 had the most significant assocaition with T2D among the three SNPs with an adjusted p value of 1.22 × 10-8 and an odd ratio of 1.58 when a recessive model was tested. The SLC30A8 gene plays the second important role among the four genes/loci in the development of T2D in Chinese Han population among the four T2D-related genes/loci in the study. However, these pre-mature conclusions require further investigaton in different Han Chinese populations.Although we could not replicate the significant association in the SNPs in the PPARG, IGF2BP2, KCNJ11, EXT2, CDKN2A/B, and LOC387761 genes with T2D, which can be explained by investigating a different population in our study. In addition, we cannot exclude the possibility of the association of other SNPs in these genes/loci with T2D in the Han Chinese population. Further studies regarding other SNPs for these genes in large Chinese populaiotns are needed to answer these questions. Because T2D is one of the most common diseases, and there are many genes invloved in the development of this disorder, each gene represents a relatively small risk or protection when they are used to assess a disease threat in a patient.