The Study Of Candidate Genes Of Primary Biliary Cirrhosis In Chinese Han Population

Primary biliary cirrhosis (PBC) is a complex autoimmune disease. Genetic susceptibility plays an important role in the pathogenesis of PBC. Recently, genome-wide association studies reveal some new susceptible genes for PBC. However, they are limited to Caucasian population. Lately, some of these genes are validated in Japanese population, and the result is diffrenet from that in Caucasian population. Neverhteless, the genetic background of PBC in Chinese Han population is not well understood. In current study, some susceptible genes of PBC were assessed in Chinses Han population. Besides, it has been found that PBC is closely related to connective tissue disease (CTD), especially Sjogren syndrome (SS). And systemic lupus erythematosus (SLE) is the most typical disease in CTD. Therefore, SS patients and SLE patients were involved in this study as disease control groups, and some known susceptible genes in SS and SLE were chosen as the tag SNPs of PBC.OBJECTIVES:We aimed to study the association of genes including IL 12A, IL12RB2, IRF5, TNFRSF1A, TNFSF4 and VDR and PBC patients, SS patients, SLE patients in Chinese Han population. And the relationship between the genotype and phenotype in PBC patients was also investigated.METHODS:221 PBC patients,250 SS patients,288 SLE patients and 393 healthy controls of Chinese Han descent were included in this study. Twenty-seven tag SNPs of the six genes were genotyped by Sequenom MassARRAY method. Data were analyzed using Haploview4.0 software, SHESIS online software and SPSS16.Osoftware.RESULTS:1. A highly significant association between IL 12A, IL12RB2, IRF5, TNFRSF1A, TNFSF4, VDR and PBC was found. SNP rs rs6441286, rs574808 and rs1800693 might be the susceptible gene loci in Chinese Han population, which resembled that in Caucasian population.2. Haplotypes GTTG in IL12A (P=0.007), TTGA in IL12RB2 (P=0.048), ACCG in TNFRSF1A and ACG in VDR were relative to disease susceptibility of PBC.3. Significant association between rs3861950 in TNFSF4 (P=0.028), rs485499 in IL12A (P=0.019) and advanced PBC were founded. Polymorphism of SNP sites of rs4760648 in VDR (P=0.021) and rs6441286 in IL12A(P=0.002) were associated with PBC patients with xerostomia and dry eye. Polymorphism of SNP sites of rs2205960 (P= 0.034) and rs 16845607 (P=0.012) in VDR were associated with the treatment effect PBC patients.4. SS patients and SLE patients shared the same susceptible gene (IRF5 and TNFSF4). No association between IL12A, IL12RB2, TNFRSF1A, VDR gene locus and disease susceptibility in SS and SLE were determined.5. The association between genes of IL12A, IL12RB2, TNFSF4, TNFRSF1A and disease susceptibility was totally different between PBC and CTD. IRF5 were associated with disease susceptibility of both PBC and CTD, but the positive SNP sites were different. Polymorphism of SNP site rs2205960 in TNFSF4 was the common risk factor in PBC, SS and SLE.6. No association between IL12A gene and high level of serum IL12 inPBC was found.CONCLUSIONS:This study first demonstrates that IL12A, IL12RB2, TNFSF4, TNFRSF1A is associated with PBC in Chinese Han population. Among these genes, TNFSF4 is the only common gene which associated with disease susceptibility of PBC, SS and SLE. Genetic polymorphism of PBC is much different from CTD. Genes of IL12A, TNFSF4 are associated with disease phenotypes of PBC.