Association study of IFNAR2 and IL10RB genes with the susceptibility and interferon response in HBV infection

Abstract

A recent genome-wide association study discovered that two polymorphisms, interferon (IFN) alpha receptor 2 (IFNAR-2) F8S and interleukin 10 receptor (IL10RB) K47E, were associated with susceptibility to hepatitis B virus (HBV) infection in Africa. Here, we reevaluate the effects of the two polymorphisms on HBV susceptibility in the Chinese Han population, and extended the study to look at their association with IFN response in chronic hepatitis B (CHB). We included 341 patients with CHB and 341 unrelated controls presenting with asymptotic HBV self-limited infection, who were well matched in age and sex. In the CHB group, 101 patients had been treated with peg-IFN-alpha-2a for 48 weeks and followed up for 24 weeks to determine the clinical response, resulting 34 individuals with sustained virological response (SVR) and 67 individuals with nonsustained response (NR). Subgroups in the CHB group were divided according to the viral loads, HBeAg and maternal HBsAg status. The association with the susceptibility to HBV infection was only observed for IL10RB K47E when we compared the individuals with persistent HBV infection through nonmaternal transmission to the controls with asymptomatic self-limited HBV infection. Further, we found that the IFNAR2-8SS genotype was associated with HBeAg negative patients (OR = 0.316, 95% CI: 0.121-0.825, P = 0.019) and that the IFNAR2-8F allele was associated with the risk to high viral loads (OR = 1.667, 95% CI: 1.148-2.420, P = 0.007). In addition, the IFNAR2-8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response (OR = 0.348, 95% CI: 0.129-0.935, P = 0.036). Haplotype analysis based on polymorphisms of three single-nucleotide polymorphisms, MxA - 88 G/T, IFNAR-2 F8S and IL10RB K47E showed that the haplotype distribution was significantly different between the SVR and NR groups (P = 0.040). This study suggests that IFNAR2 may play an important role in determining IFN response and clinical phenotypes of HBV infection in the Chinese Han population.

Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa

“…Recent studies have shown that several immunoregulatory cytokines such as IFN-γand TNF-α inhibit HBV replication through the noncytolytic process[20]. In contrast, IL-10 counteracts their effector mechanisms[8,10,11,17]. Because the capacity for cytokine production in individuals largely depends on genetic polymorphisms[21], heterogeneity of the candidate gene in patients with HBV emerges as a probable biomarker for determining the disease phenotypes.…”

“…Multivariate analyses have shown that the most important predictors of good response to IFN-αtreatment include high ALT levels, low serum HBV DNA, female gender, and histological activity on liver biopsy in chronic HBV patients[6-8]. However, despite these studies of viral factors and clinical markers affecting treatment response, the role of the host genetic background was less well studied[9].…”

“…Several proinflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-γ) and TNF-α are believed to participate in elimination of HBV [8,10,11]. In contrast, IL-10 and IL-4, Th2 cytokine, act as potent inhibitors of Th1 effectors mechanisms[8,12-14]. There are some evidences that the capacity for cytokine production in individuals has a major genetic component [15].…”

Association of Gene Polymorphisms and Serum Levels of IL-18 with the Susceptibility to Infection with Hepatitis B Virus

“…The gene loci for cytokines are defined, and polymorphisms of cytokine genes are suggested to influence the outcome of HBV infection [6]. Therefore, many recent studies have focused on the effect of gene polymorphisms of cytokines on disease outcome such as prediction of infection risk, disease progression, chronicity and response to vaccination and treatment as well as vertical transmission [7][8][9][10].…”

Interleukin 28 Receptor Gene Alpha Il28ra and Psoriasis: Association With Disease Severity and Age at Onset

“…Исследованиями установлена роль гене-тических полиморфизмов и мутаций цитокинов и цитокиновых рецепторов, а также компонен-тов их сигнальных путей в патогенезе псориаза [4][5][6][7][8]. К настоящему времени, благодаря исполь-зованию подходов анализа сцепления в семьях и полногеномных исследований ассоциаций (GWAS -genome-wide association study) в выбор-ках здоровых и больных, достигнуты определен-ные успехи в расшифровке молекулярно-гене-тических механизмов развития псориаза.…”