Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians

PURPOSE: The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. METHODS: 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. RESULTS: Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p < 0.0001), rs3749971 (OR = 1.89, 95% CI 1.21-2.94, p = 0.004) and rs1800629 (OR = 2.06, 95% CI 1.41-3.01, p = 0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR = 2.40, 95% CI 1.46-3.93, p = 0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). CONCLUSIONS: This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.