Human leukocyte antigen A1-B8-DR3-DQ2-DPB1*0401 extended haplotype in autoimmune hepatitis

Abstract

Genetic susceptibility to autoimmune hepatitis is associated with the human leukocyte antigen haplotype A1-B8-DR3 and DR4. To date, only one study in Japan has considered the human leukocyte antigen DP locus in this disease, and no studies have been reported in whites. In this study we used a series of sequence-specific oligonucleotide probes to determine human leukocyte antigen DPB1 genotypes in 101 unrelated white northern European patients and 105 racially and geographically matched controls. The aims of the study were twofold: first, to determine the degree of DPB-encoded susceptibility to autoimmune hepatitis, and, second, to establish whether susceptibility can be extended to include human leukocyte antigen DPB. None of 17 DPB1 alleles was significantly associated with the susceptibility to autoimmune hepatitis. Although one particular seven-locus haplotype A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201-++ +DPB1*0401 was significantly associated with the disease (27% vs. 7%, relative risk = 5.14, p < 0.0005), the association with this haplotype was weaker than that for the six-locus haplotype excluding DPB (40% vs. 11%, RR = 5.52, p < 0.0005). When the patients first seen at ages younger than 16 yr (pediatric patients) were considered separately, the greatest relative risk was for the seven-locus haplotype (41% vs. 7%; relative risk = 9.60, p < 0.0005). The results of this study further confirm that major histocompatibility complex-encoded susceptibility to autoimmune hepatitis is located at or close to the human leukocyte antigen DR locus; however, the A1-B8-DR3-DQ2-DPB1*0401 extended haplotype may be important in determining the age of onset and severity of disease.

Epidemiology of autoimmune liver disease

“…They also noted that the A1‐B8‐DR3 haplotype occurred in younger patients who were more likely to relapse off therapy, while DR4 was associated with older patients with seemingly milder disease. Later studies confirmed these disease associations and their respective patterns of disease, 75,76 leading to the inclusion of HLA DR3/DR4 as diagnostic criteria in the Autoimmune Hepatitis Group Revised Scoring system 28 . Subsequently, other patterns of disease have been identified with HLA typing.…”

Unraveling the Pathogenesis and Etiology of Biliary Atresia

“…For example, increased frequencies of HLA B8 and DR3 are found in patients with primary sclerosing cholangitis (61,62) and HLA A1-B8-DR3 and DR4 are risk factors for autoimmune hepatitis (63). Investigators have explored the possibility of a link between HLA type and BA with conflicting results.…”

Host genetic determinants in hepatitis C virus infection

“…Linkage between B8 and DR3 is quite strong, and this haplotype has been linked with several autoimmune diseases including autoimmune hepatitis type I, primary biliary cirrhosis and rheumatoid arthritis. [133][134][135][136][137] A few studies have also addressed the potential role of the HFE gene variants (Cys282Tyr or His63Asp polymorphisms) and iron levels. No consistent observations with respect to this locus have been observed, with several studies reporting no association between this variant and increased iron, 93,97,131 and another study reporting an association between this locus and higher mean ferritin levels.…”