Original Article

Association of Primary Sclerosing Cholangitis with HLA-DRw52a

Ernest J. Prochazka, M.D., Paul I. Terasaki, Ph.D., Min Sik Park, D.V.M., Leonard I. Goldstein, M.D., and Ronald W. Busuttil, M.D., Ph.D.

N Engl J Med 1990; 322:1842-1844June 28, 1990

Abstract

Abstract

We sought to determine whether there are specific HLA haplotypes in patients with either primary sclerosing cholangitis or primary biliary cirrhosis.

Surprisingly, 100 percent of the 29 patients with primary sclerosing cholangitis had the HLA-DRw52a antigen, which is normally present in 35 percent of the population (relative risk, 109.5; P<0.00001). Fifteen of these patients had a single common haplotype: A1,B8,Cw7, DRw17,DQw2,DRw52a. In the remaining 17 patients there was a loss of at least one of these antigens. Of the 15 patients with the common haplotype, 12 also had ulcerative colitis, thereby linking the occurrence of ulcerative colitis in patients with primary sclerosing cholangitis to the presence of this haplotype. Although there was no association in 35 patients between primary biliary cirrhosis and specific HLA haplotypes, there was a significant association of the disease with DRw8 (relative risk, 3.1; P = 0.02).

We conclude that the development of primary sclerosing cholangitis involves a strong genetic predisposition. Since the association of primary sclerosing cholangitis with HLA-DRw52a appears to be total, HLA typing should be helpful in differentiating this disease from primary biliary cirrhosis. (N Engl J Med 1990; 322:1842–4.)

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Table 1HLA Antigen Frequencies in Patients with Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis.

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Article

ALTHOUGH HLA haplotypes have been studied for more than 5000 diseases, only 3 diseases have been identified in which essentially all patients have the same HLA antigen: B27 in ankylosing spondylitis,1 , 2 DR4 in pemphigus vulgaris,3 and DR2 in narcolepsy.4 In this report, we add a fourth disease: DRw52a is present in apparently all patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis has previously been shown to be associated with the B8 and DR3 antigens,5 , 6 although in these earlier studies, no typing of the C locus or DR3β locus was performed. Our findings of an extremely high association of primary sclerosing cholangitis with the newly discovered C locus (frequency of Cw7, 86 percent) and the 100 percent frequency of DRw52a in patients with this disease suggest that the DR3β locus is closer to the critical gene that predisposes persons to primary sclerosing cholangitis.

Primary biliary cirrhosis7 may be difficult to differentiate from primary sclerosing cholangitis8 , 9 inasmuch as many clinical features are similar. An immunologic cause has been postulated for both diseases.10 , 11 In this report we confirm the association of HLA-DRw8 with primary biliary cirrhosis12 and demonstrate that the HLA antigens associated with this disease are different from those associated with primary sclerosing cholangitis.

Methods

From 1984 to 1989, 29 patients with primary sclerosing cholangitis and 35 patients with primary biliary cirrhosis were evaluated for liver transplantation at the University of California at Los Angeles. The diagnoses were based on clinical presentation; percutaneous liver biopsy, with histologic classification; endoscopic retrograde cholangiopancreatography; sigmoidoscopy; and typical laboratory findings, according to well-established criteria.7 8 9 Tissue typing was performed, and the results were compared with those for 1546 healthy, unrelated blood donors. All patients and controls were white. The comparisons were made by chi-square calculations, and the P values derived from two-tailed analysis were corrected for the number of antigens tested. The HLA antigens were determined with the standard lymphocyte cytotoxicity test.13 Tissue typing was performed for the following antigens: A locus, 1, 2, 3, 11, 23, 24, 25, 26, 28, 29, 30, 31, 32, w33, w34, and w36; B locus, 7, 8, 13, 14, 18, 21, w22, 27, 35, 37, 38, 39, 40, w41, w42, 44, 45, w47, w48, 49, w50, 51, w52, w53, w54, w55, w56, w57, w58, w59, w60, w61, w62, w63, w64, w65, w70, and w75; C locus, w1, w2, w3, w4, w5, w6, w7, and w8; DR locus, 1, 2, 3, 4, 5, w6, 7, w8, 9, w10, w11, w12, w13, w14, w15, w16, w17, and w18; DR3β locus, w52, w52a, and w53; and DQ locus, w1, w2, w3, w4, and w5.

Results

All 29 patients with primary sclerosing cholangitis had the DRw52a antigen. Since the frequency of DRw52a in controls was 35 percent, this difference was significant (P<0.00001). The assignment of DRw52a was based on the reaction of DRw52 antiserum in the presence of either DR3 or DR6. According to the nomenclature committee of the World Health Organization,14 the DRw52a antigen is also termed DR3β 0101 or Dw24.

Table 1Table 1HLA Antigen Frequencies in Patients with Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis. shows the frequencies of the most important antigens. The following antigens were all significantly associated with primary sclerosing cholangitis: A1, B8, Cw7, DRw17, DRw52a, and DQw2. Dr7 was found in one patient with primary sclerosing cholangitis (3.4 percent) as compared with 25 percent of the controls (P<0.004). DRw53 (P<0.01) and DQw3 (P = 0.02) were also found significantly less often in the patients than in the controls.

Fifteen patients with primary sclerosing cholangitis (more than half the study group) had the haplotype A1,B8,Cw7,DRw17,DQw2,DRw52a. In the remaining 14 patients there was a progressive loss of one allele in the following order: A, B, DQ, DRβ1, and C.

Of the 29 patients with primary sclerosing cholangitis, 17 also had ulcerative colitis. Ulcerative colitis was noted in 12 of the 15 patients with the haplotype A1,B8,Cw7,DRw17,DQw2,DRw52a and in 5 of the 14 in whom one or more of the antigens had been lost. The combination of ulcerative colitis and primary sclerosing cholangitis therefore had a greater association with the A1,B8,Cw7,DRw17,DQw2 haplotype than with other combinations.

The association of specific HLA haplotypes with primary biliary cirrhosis was much weaker (Table 1). The DRw8 antigen was present in 18.4 percent of such patients and only 6.9 percent of the controls (P = 0.02). In general, the antigen frequencies in patients with primary biliary cirrhosis were closer to those of the control subjects than was the case for patients with primary sclerosing cholangitis.

Discussion

There is a high frequency of HLA-B8 and HLA-DR3 antigens among patients with such apparently diverse diseases as primary sclerosing cholangitis, insulin-dependent diabetes, dermatitis herpetiformis, Graves' disease, Sjögren's syndrome, myasthenia gravis, and celiac disease. A gene linked to both B8 and DR3 may therefore be related to individual susceptibility to these autoimmune diseases. The target organ affected may be determined by another gene or by environmental factors. The present study of primary sclerosing cholangitis demonstrates a linkage with the DR3 and B8 antigens that is much stronger than that reported previously.5 , 6

Although we studied only 29 patients with primary sclerosing cholangitis, all of them had the DRw52a antigen. The entire amino acid sequence of this antigen, which is on the DR3β chain, has recently been published.15 Since all the patients had this antigen, it is likely that the determinant of disease susceptibility is on position 26 (tyrosine), 38 (leucine), 57 (valine), or 60 (serine), all of which are unique to DRw52a. Thus, in addition to the HLA association, we have now been able to pinpoint the specific sites on the HLA molecule related to the susceptibility to primary sclerosing cholangitis. This relation is analogous to the association found earlier between insulin-dependent diabetes and residue 57 of the DQ1β chain.16

Although primary sclerosing cholangitis is clinically similar to primary biliary cirrhosis,10 our histocompatibility testing shows that the two diseases occur in patients with different genetic constitutions. Primary sclerosing cholangitis appears to be similar to chronic active hepatitis in the absence of hepatitis B surface antigen,17 , 18 since both are found in association with a high frequency of DR3 and Cw7. As for the possibility of a viral cause, it is interesting that primary sclerosing cholangitis has been found in relatively large numbers of patients with the human immunodeficiency virus.19

Ulcerative colitis has often been studied for HLA linkage; some studies have indicated no association,20 whereas others have shown an association with HLA-DR3 and HLA-B8.6 The present finding that primary sclerosing cholangitis in combination with ulcerative colitis is found primarily in patients with the key extended haplotype of A1,B8,Cw7,DR3,DQw2, DRw52a suggests that at least one form of ulcerative colitis is a manifestation of the autoimmune haplotype. There is probably also a form of the disease that is not associated with the HLA haplotype.

Source Information

From the Departments of Surgery (E.J.P., P.I.T., M.S.P., R.W.B.) and Internal Medicine (L.I.G.), UCLA School of Medicine. Los Angeles. Address reprint requests to Dr. Terasaki at the Department of Surgery, UCLA Tissue Typing Laboratory, 950 Veteran Ave., Los Angeles, CA 90024.

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