Association of the CTLA4 gene with Graves' disease in the Chinese Han population

Abstract

To determine whether genetic heterogeneity exists in patients with Graves' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81x10(-9), OR = 1.35, and genotype distributions p = 2.75x10(-9), OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.

Figure 1. The results of association analysis of SNPs in the CTLA4 gene region from different populations.

A total of 47 SNPs located in the CTLA4 gene region were genotyped in all subjects from different geographic regions of China. After removal of the SNPs with minor allele frequencies (MAF) <1%, missing data above 20% or HWE p≤1×10⁻⁶ in the controls, the allele frequencies (A) and genotype distributions (B) in GD and control subjects from different populations were plotted [−log10(p value) against location]. The most significantly associated SNPs in the combined Chinese Han, Xuzhou, and southern populations were all located at rs231779, with the smallest p values of 2.81×10⁻⁹, 1.37×10⁻⁵, 0.0071 in allele frequency difference (A) and 2.75×10⁻⁹, 1.55×10⁻⁵, 0.0013 in genotype distributions (B), respectively. In the Shandong population the most significantly locus was located at rs35219727, with the smallest p values of 1.30×10⁻⁵ in allele frequencies (A) and 3.57×10⁻⁷ in genotype distributions (B) (see Tables 1 and 2 for detailed information). C–F: Two-locus logistic regression analyses of rs231779 in the combined Chinese Han population (C), rs35219727 in the Shandong population (D), rs2321779 in the Xuzhou population (E) and rs231779 in the Southern China population (F). SNPs rs231779 and rs35219727were put individually into the regression models as the best makers, and all other markers were sequentially added to see if a second locus could improve the model. In the combined Chinese Han population, three of the 14 SNPs suitable for logistic regression analysis hurt the model with rs231779 (C), at the p value <0.01. In contrast, we tested a regression model by taking each of 14 loci in turn and adding the test locus to it. All the markers could be improved by adding rs231779 (C). At the same time, in the Shandong population, rs35219727 improved the model with each of the other 14 SNPs; however, seven SNPs hurt the model with rs35219727, except SNP rs11571316 (D) (see Table 3 for detailed information). In the Xuzhou and Southern China populations, most of the models with other SNPs could be improved by adding SNP rs231779, however, no or only two SNPs can improve the model with rs231779 (E, F). G–J: The SNPs linkage disequilibrium (LD) region for the Combined Chinese Han (G), Shandong (H), Xuzhou (I) and the southern China (J) populations in the CTLA4 gene region were analyzed with haploview software.