Analysis of HLA alleles in Japanese patients with cirrhosis due to chronic hepatitis C

Abstract

Hepatitis C virus (HCV) leads to chronic liver disease in at least 50-60% of infected people and approximately 40-50% of these patients will go on to develop cirrhosis due to chronic hepatitis C (HCV-C). The pathogenic mechanisms that result in HCV-C are unknown. Sixty Japanese patients with HCV-C were examined for HLA-A, B, C and DR alleles by serologic typing and for HLA-DQB1 alleles by DNA typing using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. As the control population, 293 healthy un-related Japanese were used. The frequencies of HLA-B61, C(omega)3, DR4, DQB1*0401 and DQB1*0402 were increased, while those of HLA-DR9, DQB1*0301 and DQB1*0303 were decreased in the patients. The co-ordinate increase in the frequency of HLA-DR4, DQB1*0401 or 0402 and decrease in the frequency of DR9 or DQB1*0303 were suggestive of a strong linkage disequilibrium between HLA-DR4 and DQB1*0401 or 0402 and between HLA-DR9 and DQB1*0303, respectively. From the odds ratio (OR) analysis, the combinations of HLA-C(omega)3+ DR4-DQB1*0401 or 0402, or HLA-B61 + DR4 - DQB1*0401 or 0402 increased the risk for developing HCV-C when compared to each HLA allele alone. This suggested an additive effect for these classes I and II HLA allele combinations in HCV-C. In contrast, HLA-DR9-DQB1*0303 and DQB1*0301 may confer resistance to this disease. These results suggest the existence of HLA-linked susceptibility genes to HCV-C.

Association of Human Leucocyte Antigen Class I (HLA-A and HLA-B) With Chronic Hepatitis C Virus Infection in Egyptian Patients

“…The associations between HLA Class I antigens and the outcome of HCV infection are extensively investigated in different ethnic populations such as Caucasian Americans and populations from Korea, Italy, Russia, Spain, Ireland, Saudi Arabia, Western India, Japan and Germany [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. The earlier reported associations showed ethnic and geographical differences sometimes with contradictory results.…”

Chronic viral hepatitis and the human genome

“…In a German study, DRB1*1302, which is associated with slower disease progression, 19,21 was shown to have decreased frequency in HCV-infected individuals compared with controls. 27 DR4 and DQB1*0401 were more frequent in Japanese HCVinfected subjects compared with random controls, 26 and in a Japanese study of progression, both of these alleles are associated with more rapid progression. 62 A comparison of results in each of the three outcomes presents a wide array of HLA alleles that are associated with HCV infection.…”

“…Several studies have attempted to examine susceptibility to HCV infection by comparing HLA alleles in individuals who are anti-HCV-positive with either the general population or with people who are anti-HCVnegative (Table 4). [25][26][27][28][29]31,[63][64][65] Because the assumption cannot be made that the general population has been exposed to HCV, true associations may be missed by this experimental design. In addition, identification of individuals who have been exposed to HCV but remain seronegative is difficult.…”

“…The haplotype DRB1*1601-DQB1*0502 was more frequent in the HCVnegative thalassemic controls relative to the anti-HCV-positive individuals. Several other studies have identified associations between class I and/or class II alleles and HCV infection, [25][26][27][28][29] but class I typing was performed using serological techniques, and controls always involved individuals who were unlikely to have been exposed to the virus. In general, among these studies, many different HLA associations were identified, but a few supported data from studies of HCV clearance and progression.…”

“…3 Most studies to date of HBV and HCV have employed this method of study, but difficulties involved in designing such studies include an inappropriate control group (detailed later) or a small number of study participants. [14][15][16][17][18][19][20][21] The control group in most of the viral hepatitis studies is from the general population [22][23][24][25][26][27][28] or from blood or bone marrow donors, [29][30][31] which can lead to a misclassification bias because some of these individuals may not have been exposed to the virus. In such cases, true associations may be missed because unexposed subjects capable of becoming infected are included as controls.…”