Associations Of The 4P14 And CTLA-4 Gene Polymorphisms With Graves' Disease

Objective To investigate the associations of the rs6832151 within chromosomal band 4P14 and four single-nucleotide polymorphisms(SNPs)in CTLA-4 gene with Graves' disease(GD)in a Chinese Han population from Bengbu city,Anhui province,as well as gene-gene interaction on Graves' disease.These studies are to further reveal the pathogenesis of Graves.Methods1.611 patients with Graves disease who were treated in the Department of endocrinology of the First Affiliated Hospital of Bengbu Medical College were selected as the case group.All the patients had no blood relationship and met the diagnostic criteria of Graves disease.There were 644 cases in the control group who made physical examination in the First Affiliated Hospital of Bengbu Medical College.The healthy people who were over 40 years old(excluding late onset autoimmune disease),without any blood relationship and well matched in sex all came from Bengbu area.All of the healthy people were treated by the determination of thyroid hormone,TSH receptor antibodies,thyroid peroxidase antibody,thyroglobulin antibody level to rule out thyroid disease.2.The clinical data and peripheral blood 5ml of all subjects were collected,and extract DNA from the peripheral blood.A total of five SNPs were genotyped in a cohort of 611 GD patients and 644 healthy controls,by using the Taq Man SNP Genotyping Assay.3.We should make correlation analysis,linkage analysis,haplotype analysis,Hardy-Weinberg genetic equilibrium test,epistasis analysis and gene-gene interaction analysis by SPSS18.0 software,Haploview 4.2 software,PLINK v1.07 software and GMDR0.9 software.Results1.An association was observed when the rs6832151 was directly analyzed or analyzed under three genetic models between GD and controls(P<0.05).The frequencies of genotypes under dominant model of SNPs in CTLA-4(rs231804,rs231726)were significantly different between GD and controls(?~2=4.37,P=0.037;?~2=5.06,P=0.025).2.There were obvious linkage disequilibrium between rs1024161 and rs231726(r2=0.759,D'=0.993)?rs1024161 and rs10197319(r2=0.545,D'=0.85)?rs231726and rs10197319(r2 =0.496,D'=0.925)?rs231804 and rs1024161(r2=0.437,D'=0.987)?rs231804 and rs231726(r2 =0.338,D'=0.99).In contrast,there was no obvious linkage disequilibrium between rs231804 and rs10197319(r2=0.077,D'=0.36).The frequency distribution of haplotypes of SNPs in CTLA-4(AA)was statistically significant different between the GD patients and controls(?~2=5.077,P=0.0242).3.Significant epistasis was found between rs1024161 and rs10197319 in CTLA-4(P=0.018).4.In the GMDR analysis,the five-order interaction of CTLA-4(rs10197319?rs231726?rs231804?rs1024161)and 4P14(rs6832151)was the best model.Gene-gene interactions among them on Graves' disease were significant(P=0.001).Conclusions1.Polymorphism of the rs6832151(4P14)?rs231804 and rs231726(CTLA-4)are susceptible gene to Graves' disease for a Chinese Han population from Bengbu city.2.The haplotype in CTLA-4 is associated with Graves' disease.Epistatic interaction is observed between rs1024161 and rs10197319 in GD.3.A gene-gene interaction on Graves' disease is identified among rs10197319?rs231726?rs231804?rs1024161(CTLA-4)and rs6832151(4P14).