Polymorphisms in the IL-12B Gene and Outcome of HCV Infection

Abstract

Most people with hepatitis C virus (HCV) develop chronic infection with persistent viremia. Resolution of infection is associated with antiviral cellular immune responses of T helper 1 (Th1) type. Interleukin-12 (IL-12) is a key cytokine in the generation of Th1 responses, and functionally relevant polymorphisms of the IL12B gene and its promoter have been described recently. We sought an association between three IL12B polymorphisms and outcome of HCV infection in 195 HCV antibody-positive patients; 123 were chronically infected with detectable HCV RNA, and 72 had spontaneously resolved infection testing repeatedly negative for HCV RNA. Genotyping was performed for a single nucleotide polymorphism (SNP) in the 3'-UTR (1188A/C) of the IL12B gene and for 4-bp insertion/deletion polymorphisms in the IL12B promoter region and in the intron 4 region of the IL12B gene. We found chronically infected patients were significantly more likely than those with resolved HCV infection to be homozygous for the 3'-UTR A allele (66% vs. 50%; chi-square = 4.12, p = 0.04 with Yates correction), which has been associated with lower IL-12 production. No other significant association was found. Our findings support the concept that an individual's genetically determined ability to produce IL-12 is another factor that can influence the outcome of HCV infection.

Hemophilic Siblings With Chronic Hepatitis C: Familial Aggregation of Spontaneous and Treatment-Related Viral Clearance

“…Nevertheless, this information provides additional support for a relationship between host genetics and HCV viral clearance and is consistent with several recent reports that evaluated gene expression and gene polymorphisms in individuals with and without sustained virological response to interferon-based regimens (49)(50)(51)(52)(53)(54). Using microarrays in hepatic tissue, Chen and colleagues identified a number of interferon-sensitive genes that correlated with response to antiviral therapy (50).…”

A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants

“…Given the central role of T cells in viral control and clearance in general (reviewed by Bowen and Walker 2005;Klenerman and Hill 2005) and the pivotal role of IL12 in the generation of the Th1 response in particular, three groups have postulated that the IL12B A/C SNP could affect spontaneous and treatment-induced recovery from hepatitis V virus (HCV)-infection. Their results [the A/A genotype was found to be associated with persistent infection (Yin et al 2004;Houldsworth et al 2005) whereas the C allele was associated with a more efficient response to antiviral combination therapy as a consequence of a reduced relapse gap (Mueller et al 2004)] suggests that the C allele may act as a protective factor with respect to the outcome of HCV infection. However, the A/C SNP does not appear to be a susceptibility factor for HCV infection since its distribution did not significantly differ between patients and healthy controls (Mueller et al 2004).…”

Osteopontin as a marker for response to pegylated interferon Alpha-2b treatment in Chronic HCV Saudi patients

“…Th1 immune response is involved in the development of inflammation in chronic hepatitis C, and the hepatocytes infected with HCV are eradicated by Th1 response during IFN-based therapies 6 . Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation that has been employed for the prediction of both disease progression 7 and therapeutic response 8 . Also, SNP was reported to be associated with a virologic response to IFN-based therapy 9 .…”