A single nucleotide polymorphism of the low molecular mass polypeptide 7 gene influences the interferon response in patients with chronic hepatitis C

Abstract

Transporter associated with antigen processing (TAP) and low molecular mass polypeptides (LMP) play crucial roles in the human leukocyte antigen (HLA) class I-restricted antigen presenting systems. This study was performed to elucidate whether these antigen-presenting gene polymorphisms could influence the response to interferon (IFN) treatment in patients with chronic hepatitis C. Polymorphisms of TAP and LMP genes in 175 hepatitis C virus (HCV) patients were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of these genes were compared between sustained-responders (n=49) and nonresponders (n=126), classified by biochemical and virological responses to IFN. The distributions of TAP1*, TAP2*, and LMP2 genes between sustained-responders and nonresponders did not differ. However, LMP7-K gene frequency in sustained-responders was higher than that in nonresponders [odds ratio 2.3 (95% confidence interval 1.1-4.6); 16%vs 7.9%]. Multivariate analysis revealed that LMP7-K and HCV-RNA quantity were independent factors influencing the outcome of IFN therapy [4.5 (1.4-14); P=0.011, 0.40 (0.24-0.65); P=0.0003, respectively]. Furthermore, among patients with a low viral load (< or = 2.0 Meq/mL), the LMP7-K positive patients had an even higher ratio of sustained response compared to those without LMP7-K [5.9 (1.6-22); 82%vs 44%; P=0.0062]. These findings suggest that a single nucleotide polymorphism of LMP7 gene is one of the important host factors which independently influence the response to IFN in patients with chronic hepatitis C.

Haplotype-taggingRANTES gene variants influence response to antiviral therapy in chronic hepatitis C

“…Few studies have investigated variations in other gene loci in relation to outcome of the antiviral therapy for chronic HCV infection, including cytokine genes, 36 -40 the mannose-binding lectin gene, 41 the gene for interferoninducible MxA protein, 42 the low molecular mass polypeptide 7 gene, 43 and the low-density lipoprotein receptor. 44 However, all of these studies had less than 80% power to detect moderate effects of gene variants because of a sample size of less than 100 individuals per subgroup.…”

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

“…42,43 Fewer functional studies have been performed on LMP polymorphisms; however, it has been reported that the LMP2 R60H and LMP7 Q49K polymorphisms (in this report) affect age-dependent TNF-a apoptosis and response to interferon in patients with chronic hepatitis C, respectively. 44,45 Immunoproteasomes might also play an integral role in maintaining peripheral tolerance. Immunoproteasomes are constitutively expressed in the thymus and by mature dendritic cells under conditions in which most T-cell activation occurs, whereas elsewhere in the periphery constitutive proteasomes are expressed in the absence of inflammation.…”

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

“…Polymorphisms in several genes including MxA, PKR, OAS, 11 HLA, KIR, TNF, 12 and MICA have been shown to be associated with HCV clearance or persistence. 13,14 Studies have indicated that single nucleotide polymorphisms (SNPs) in the IL10, CTLA, MxA, and LMP7 genes may influence the response to IFN-a treatment in patients with chronic HCV [15][16][17] along with variants in the HLA. 13,14 The strength of the immune response may influence HCV-mediated fibrogenesis 10 through cytokines that stimulate extracellular matrix deposition such as TNF.…”