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

Abstract

PurposeThe 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.Methods77 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.ResultsSignificant 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).ConclusionsThis 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.

Hepatitis mouse models: from acute‐to‐chronic autoimmune hepatitis

“…; Ngu et al . ). Furthermore, environmental factors including infections with hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), herpes simplex virus (HSV) or bacteria ( Listeria monocytogenes ) (Limmer et al .…”

“…Approximately 45-80% of patients with AIH will progress to cirrhosis, of which 4% will develop hepatocellular carcinoma (HCC) (Czaja 1995;Mizutani et al 2005;Longhi et al 2010;Oo et al 2010). In 40% of patients with AIH, copresentation with other autoimmune disorders such as thyroiditis, ulcerative colitis, type 1 diabetes and rheumatoid arthritis and overlap syndromes including primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangitis is observed (Czaja 1995; Although the initial trigger causing AIH is unknown, it is widely accepted that genetic factors, such as HLA-DR3 or HLA-DR4 haplotypes, are risk factors Ngu et al 2013). Furthermore, environmental factors including infections with hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), herpes simplex virus (HSV) or bacteria (Listeria monocytogenes) (Limmer et al 1998a,b;Longhi et al 2010) and drugs such as nitrofurantoin and minocycline (Bjornsson et al 2010) can trigger hepatitis onset/development.…”

Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

“…3,[15][16][17][18][19] No independent and reproducible associations outside the MHC have been identified. [20][21][22][23][24][25][26][27][28] Since genome-wide association studies (GWASs) have emerged as a powerful and unbiased approach for the identification of new genetic susceptibility loci in autoimmune diseases, 29 we applied this methodology in a large cohort of AIH patients and controls and replicated the identified loci in an independent set of patients and controls.…”

Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population

“… 22 Multiple studies failed to show any significant association of the +49 A/G polymorphism with autoimmune hepatitis susceptibility and onset. In fact, a study realized 25 in New Zealand included 77 autoimmune hepatitis patients and showed no statistically significant association between the CTLA4 +49 gene polymorphism and the occurrence of autoimmune hepatitis. Other studies that have examined the implication of +49 A > G polymorphism CTLA4 (rs 231775) with AIH onset have failed to show a definitive association between CTLA4 A/G polymorphism and disease susceptibility in Brazilian, Chinese, Japanese or Netherlandic populations (Bittencourt et al.…”