The present study demonstrated an increase in the GG frequency as well as a decrease of the GA frequency in female HCV patients, in particular, in those RNA+ patients with elevated levels of ALT. Additionally, we found an increased frequency of the GA genotype in self-limited HCV infection.
In spite of ethnic differences, our results are in line with similar findings reported by the Mayo Clinic (30
) and by an extensive study performed in the United Kingdom (10
). These studies have also found that the GG frequency increased in patients with chronic HCV infection. Also in accordance with our report, the ATA haplotype (15
) and ATA/ATA and −1082A/G genotypes (10
) were found to be associated with the self-limited infection.
This study addressed for the first time the gender effect in the association between IL-10 promoter polymorphism and the HCV infection. Our understanding is that the gender effect described in the present study might explain many contradictory reports regarding the effect of the IL-10 promoter associated with HCV infection. As examples of these contradictory results, Edwards-Smith et al. (5
) found no significant differences in genotype frequencies including a gender effect, but the small number of patients analyzed might preclude detection of this effect. Along the same lines, additional reports were unable to confirm differences in the haplotype or genotype frequencies between patients and controls (15
). However, those studies failed to analyze a gender effect or also were based on a small number of cases. On the other hand, Lio et al., whose study was based on data from only 60 HCV patients (18 RNA−
and 42 RNA+
patients), reported that the GG genotype was associated with a self-limited HCV infection (14
A vigorous CD4+
T-cell response with a predominant Th1 cytokine profile seems to be responsible for recovery from an HCV infection (4
). Conversely, patients who develop a chronic infection show a predominant Th2 response that down-regulates the Th1 response and therefore favors persistent HCV infection (6
). In this context, it is tempting to speculate that those individuals carrying the high IL-10 producer genotype (GG) will be prone to down-regulate the Th1 response, resulting in a failure of the HCV clearance.
Experimental and clinical data suggest a protective role of IL-10 in hepatic fibrogenesis (20
). Accordingly, we found that the increased frequency of GG was observed only with noncirrhotic female patients, mainly in those with stages 1 and 2 of liver fibrosis (not shown), but not in patients with stage 4 (cirrhosis). A study of Japanese chronically HCV-infected patients reported the GCC haplotype to be associated with less hepatic fibrosis. In line with our findings, this Japanese study suggests that high production of IL-10 may cause inhibition of liver fibrosis progression (7
Chronically HCV-infected patients who received a short treatment with recombinant IL-10 showed a decreased hepatic inflammation and reduced liver fibrosis (20
). On the other hand, and in concordance with our findings, a 12-month IL-10 therapy in patients with advanced fibrosis led to increased levels of serum HCV RNA and a reduction in fibrosis score (21
), suggesting that high levels of IL-10 not only decrease fibrogenesis but also lead to an increased HCV viral burden. This could be achieved by decreasing the number of HCV-specific CD4+
gamma interferon-secreting T cells and polarizing the immune response towards a Th2-dominant profile.
Similarly, it has been published that the antibody-induced blockage of the IL-10 receptor generates a favorable balance of CD4+
T-cell response to HCV. Also, this anti-IL-10 receptor reverses the inhibitory effect of IL-10 on HCV-specific T-cell proliferation, demonstrating the major role of IL-10 in suppressing antiviral T-cell responses (28
). Moreover, clinical evidence suggests that individuals with cellular immune dysfunction, such as that due to HIV infection, show a much faster disease progression (11
In conclusion, the present study confirms that the host's genetic background plays a significant role in the outcome of HCV infection. In particular, we demonstrate a gender effect associated with the susceptibility to develop a persistent HCV infection and a chronic liver disease together with an inhibition of fibrogenic process in women carrying the GG IL-10 promoter genotype.