From Journal of Viral Hepatitis
IL28B Genetic Variants and Gender Are Associated With Spontaneous Clearance of Hepatitis C Virus Infection
H.-Y. Rao; D.-G. Sun; D. Jiang; R.-F. Yang; F. Guo; J.-H. Wang; F. Liu; H.-Y. Zhang; H.-H. Zhang; S.-C. Du; Q. Jin; H. Qin; A.-S.-F. Lok; L. Wei
Posted: 03/28/2012; J Viral Hepat. 2012;19(3):173-181. © 2012 Blackwell Publishing
Discussion Only
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In this study of 376 HCV-infected Chinese paid plasma donors, we found that IL28B gene variants were significantly associated with the spontaneous clearance of HCV infection. The SNP that had the strongest association with spontaneous clearance of HCV infection was rs8099917, and persons with the TT genotype were 15 times more likely to clear HCV than those with the GT genotype. However, the SNP rs12979860 that has been shown to be most strongly associated with response to pegylated interferon and ribavirin and to spontaneous HCV clearance in Caucasians and African Americans was not associated with spontaneous
HCV clearance in our study.[10–14]
Thomas et al. [14] studied 1008 subjects in six independent cohorts and found that rs12979860 CC genotype was predictive of spontaneous HCV clearance among individuals of both European and African ancestry. An association between rs12979860 CC genotype and spontaneous HCV clearance was also shown by Tillmann et al. [16] who studied 190 German women and by Montes-Cano et al. [18] in a study of 353 Spanish subjects. In all three studies, only one SNP (rs12979860) was tested. An association between rs8099917 TT genotype and response to pegylated interferon and ribavirin treatment had been reported in the studies of Caucasian patients and Japanese patients with chronic HCV infection.[11,12,17] An association between rs8099917 TT genotype and spontaneous clearance of HCV infection was also demonstrated in a study of 132 predominantly Caucasian patients in Australia and a study of 1362 Swiss and German patients.[12,15] Only two SNPs (rs8099917 and rs12980275) were tested in the study in Australia. The study in Switzerland tested more than 500 000 SNPs. Analysis of data from 1213 individuals with available data at both rs12979860 and rs8099917 found that rs12979860 genotype was highly associated with chronic HCV infection and was in strong linkage disequilibrium with rs8099917.[12]
In this study, we tested eight SNPs and found an association between spontaneous HCV clearance and four SNPs including rs8099917, rs8105790, rs12980275 and rs10853728 but not rs12979860. Ge et al. [10] had noted that the linkage between rs8099917 and rs12979860 is high among Caucasians, but low among African Americans. We found that rs8099917 was strongly linked to rs12979860 (r 2 = 1.00), rs12980275 (r 2 = 0.97) and rs8105790 (r 2 = 1.00) in our study. In our study, all donors with rs12979860 CC had rs8099917 TT genotype, but donors with rs12979860 CT could be rs8099917 TT or TG.
The rs12979860 C allele frequency in the Chinese Han population (83 subjects from Beijing, China) was reported to be 93.4% in HapMap and 94–98% in Thomas' study of 47 Chinese in Taiwan and 59 Chinese in San Francisco, but it was only 74% in our study. The rs8099917 T allele frequency in the Chinese Han population was reported to be 93.5% in HapMap and 93.3% in our study. The subjects in our study all came from one county, Hebei, in the northern part of China. So, the SNP allele frequencies in our study might be only representative of the northern local region. While most Chinese in the major cities of China are of Han ancestry, other ancestries predominate in some parts of China. Studies involving larger numbers of Chinese in different regions of China are necessary to determine the precise frequency of the favourable alleles at rs12979860 and rs8099917 among Chinese of various ancestries.
In this study, the SNP rs8099917 had the strongest association with spontaneous HCV clearance. Although three other SNPs (rs10853728, rs 12980275 and rs8105790) in the IL28B region were independently associated with spontaneous HCV clearance, inclusion of these three SNPs or the haplotype ATTC with favourable alleles at these three SNPs plus rs8099917 did not improve the prediction of spontaneous HCV clearance in the multivariate model compared with rs8099917 alone. Several studies showed that women were more likely to undergo spontaneous HCV clearance than men. One study of 67 persons with acute HCV infection, 66% of whom were injection drug users, found that HCV clearance occurred in 34% of women compared with 3% of men (P < 0.001).[20] Another study followed 135 injection drug users with incident HCV infection and found that the age-adjusted hazard ratio of spontaneous HCV clearance for women was 2.91 (95% CI: 1.68–5.03).[21] A systematic review of 31 longitudinal studies that included 314 subjects showed that the relative risk of spontaneous HCV clearance for men was 0.43 (95% CI: 0.36–0.53) (P = 0.00001).[22]
Two recent studies examined gender, IL28B genetic variants and spontaneous HCV clearance. In Grebely et al.'s[15] study of 132 Australians, rs8099917 TT genotype (adjusted hazard ratio 3.78, 95% CI: 1.04–13.76) was the only factor predicting spontaneous HCV clearance on multivariate analysis, but female gender and jaundice during the acute illness were not. In Montes-Cano et al.'s[18] study of 352 Spanish subjects, rs12979860 CC genotype was associated with a higher rate of spontaneous HCV clearance in both men (72.4%vs 27.6%) and women (72.5%vs 27.5%) compared with those with CT or TT genotype. In this study, we found that women had a higher rate of spontaneous HCV clearance than men, 26.3%vs 14.6%, and this difference persisted even after stratification for IL28B genotypes. Among those with rs8099917 TT genotype, women were twice as likely to have spontaneous HCV clearance as men. Female gender remained an independent predictor of spontaneous HCV clearance in the multivariate model, with OR of 1.95.
Some studies found that the presence of jaundice or symptoms during acute HCV infection was associated with a higher rate of spontaneous HCV clearance.[15,16,22] Tillmann et al. [16] found that jaundice during acute infection was associated with an increased chance of spontaneous HCV clearance (42.9%vs 13.7%) in persons with non-CC genotype at rs12979860, but not in those with CC genotype (56.3%vs 60.6%). In this study, spontaneous HCV clearance rate was similar in donors with and without documented ALT elevation during the outbreaks, but the donors were not regularly monitored, and it is possible that ALT was not tested at the time of acute infection. We were also not able to determine whether any of the donors had symptomatic illness or were jaundiced during the acute infection.
In summary, in this study of a large homogenous cohort of HCV-infected plasma donors, we found that 21.3% had spontaneous HCV clearance. We confirmed that IL28B genotype is associated with spontaneous HCV clearance with rs8099917 TT genotype showing the strongest association, while rs12979860 CC genotype had no association. Women had a higher rate of spontaneous HCV clearance regardless of IL28B genotype. Our results suggest that while IL28B genotype is associated with spontaneous HCV clearance in patients of diverse racial/ethnic background, the SNP with the strongest association may vary. Further studies are needed to confirm this observation and to clarify whether other factors such as gender and severity of the acute illness are independent predictors of spontaneous HCV clearance after correction for IL28B genotype. These results will help in determining which patients with acute HCV infection should start on antiviral therapy and which ones to be monitored.
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