Amino acid substitutions at position 38 of the DRβ polypeptide confer susceptibility to and protection from primary sclerosing cholangitis

Abstract

Previous studies based on serological HLA phenotyping have implicated genes in the HLA class II region in susceptibility to and protection from primary sclerosing cholangitis. In a recent report, the HLA DRw52a antigen was present in all 29 patients who had been referred for liver transplantation. In this study, HLA DRB, DQA and DQB genotypes were studied using gene amplification and sequence-specific oligonucleotide probing in 71 patients with primary sclerosing cholangitis and 68 healthy controls to determine the frequency among the patients of the DRB3*0101 allele that encodes DRw52a and whether other class II alleles are involved in susceptibility or protection. DRB3*0101 was the most strongly associated allele, being present in 55% of the patients and 22% of the controls. Survival among the DRB3*0101-positive patients was reduced compared with the DRB3*0101-negative patients. Both DRB3*0101 and DRB5*0101, a possible second DRB susceptibility allele, encode a leucine residue at position 38 of the DR beta molecule. The DRB4*0101 allele, which encodes DRw53 and may be protective, encodes an alanine residue at this position. Susceptibility to and protection from primary sclerosing cholangitis may result from amino acid substitutions at position 38 of the DR beta molecule because maximum relative risk was conferred by two leucine-38-containing DR beta molecules, whereas minimum relative risk was conferred by two alanine-38-containing molecules.

Primary sclerosing cholangitis

“…12 The occurrence of PSC in members of the same family and definite HLA association suggest a genetic predisposition for developing this disease. Although our knowledge of immunogenetic susceptibility in PSC is incomplete and further work is needed, susceptibility to PSC seems to be determined by HLA DRB1*0301 (DR3) and DRB3*0101 (DRw52a) alleles, [13][14][15] while the DRB1*0401 (DR4) allele may be a marker of more rapid disease progression. 14,16 The aberrant expression of class II HLA antigen on bile duct epithelium may be secondary to biliary obstruction and not an underlying event.…”

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

“…5,[7][8][9][10] We therefore investigated whether the observed increased frequencies of MICA5.1 and MICB24 were independent of PSC association to HLA-DR3, by analyzing the distribution of MICA5.1 and MICB24 among DR3-positive and DR3-negative individuals. In the present study, 56% of the patients carried DR3 compared with 24% of the controls (OR ϭ 4.1; P c Ͻ 1 ϫ 10 Ϫ7 ).…”

“…The frequencies of genes encoding HLA-B8 in the class I region and the DR3 (DRB1*03, DQA1*05, DQB1*02), DR2 (DRB1*15, DQA1*0102, DQB1*0602), and DR6 (DRB1*13, DQA1*0103, DQB1*0603) haplotypes of the class II region are increased in PSC patients. [5][6][7][8][9][10] However, there is strong linkage disequilibrium in the HLA region, and it has not yet been established whether it is the associated HLA genes per se or closely linked genes that are responsible for the primary disease susceptibility to PSC.…”

Human leukocyte antigen associations in Finnish liver transplantations due to primary sclerosing cholangitis and primary biliary cirrhosis

“…An increased frequency of the allele DRB1*0301, which encodes the serological determinant HLA-DR3, and the allele DRB1*1301 encoding the serological determinant HLA-DR6, have reproducibly been shown to be associated with PSC [10][11][12]. The association of DRB1*0301 with PSC has been replicated in other studies [13,14]. In a study of 265 PSC patients from five European countries, HLA-DR3, -DQ2 heterozygous genotype associated with a more rapid progression of PSC [15].…”

“…When secondary HLA associations were sought by eliminating all of the patients and controls positive for the primary associated allele or alleles and reanalysing the data, increased HLA-DR2 (DRB1*1501 allele) frequency was observed in PSC patients [11,14]. HLA-DR4 has been found to negatively associate with PSC [10,11,13,14], suggesting a protective effect of this allele, but, on the contrary, rapid disease progression has been observed in a study in HLA-DR4 positive PSC patients [14].…”