Association of Single Nucleotide Polymorphisms of the Interleukin-10 Promoter Gene and Susceptibility to Primary Biliary Cirrhosis: Immunogenetic Differences in Italian and Japanese Patients

Abstract

Several lines of data suggest that genetic factors play an important role in the onset and/or progression of primary biliary cirrhosis (PBC). Since PBC is an autoimmune disease, it is reasoned to assume that genes encoding cytokines may confer susceptibility to disease. Amongst these factors, interleukin-10 (IL-10) has received significant attention. The promoter region of IL-10 gene has three single nucleotide polymorphisms (SNPs) at positions -1082, -819 and -592. To elucidate the association of the three SNPs of IL-10 promoter region with susceptibility of PBC in two different genetic populations, 159 unrelated patients with PBC (94 Italian and 65 Japanese) and 143 local controls (72 Italian and 71 Japanese) were enrolled. SNPs were determined using allele-specific PCR/RFLP. In Italian PBC patients, the frequency of homozygosity for G/G at position -1082 was significantly higher than that of local controls (p < 0.041, OR = 2.44, 95% C.I.; 1.02-5.86). The frequencies of haplotype GCC in PBC patients, possibly linked to higher IL-10 production, were also significant higher than local controls (p < 0.033). However, in Japanese population, there were no significant differences in the three SNPs and haplotypes between PBC patients and controls. Excessive production of IL-10 may play an important role in some populations in modulating the onset of PBC. Further, immunogenetic studies of PBC should take into account ethnic and geographic variations; this makes such studies in heterogeneous population, like the USA, more difficult.

Genes and (auto)immunity in primary biliary cirrhosis

“…63 Further, based on experimental evidence of cytokine profiles and its involvement in the development of T helper 1 (Th1) cell responses, SNPs of the promoter region of the IL-10 gene were also analyzed in patients with PBC and controls. 55,63,64 Data from Italian and Japanese series demonstrated that both groups presented a higher prevalence of the À1082G/G genotype. 64 Such association was not confirmed in 77 Chinese patients with PBC.…”

“…55,63,64 Data from Italian and Japanese series demonstrated that both groups presented a higher prevalence of the À1082G/G genotype. 64 Such association was not confirmed in 77 Chinese patients with PBC. 62,63 SNPs of the 1,25-dihydroxyvitamin D receptor (VDR) gene have been investigated in several studies, based on the dual role of vitamin D in the regulation of bone metabolism and inflammation.…”

Genome-Wide Association Studies in Primary Biliary Cirrhosis

“…A number of non-HLA candidate gene studies in PBC interrogated genes known or suspected to be involved with autoimmunity including TNF, CTLA4, PTPN22, PDCD1, IL1, IL2, IL10 , toll like receptors and the vitamin D receptor 26–34 . Many of these studies were limited by inadequate power and poor gene coverage (often just a single SNP) and there was little correlation between studies.…”

Genomic variants associated with primary biliary cirrhosis

“…The latter group, however, more recently described an association of PBC with the IL1-RN intron genotype, comparing frequencies in 77 patients with PBC and 160 controls [62]. Further, based on experimental evidence of cytokine profiles and their involvement in the development of T helper 1 cell responses, SNPs of the promoter region of the IL-10 gene were also analyzed in patients with PBC and controls [53,62,63]. Data from Italian and Japanese series demonstrated that both groups presented a higher prevalence of the -1082G/G genotype [63].…”

“…Further, based on experimental evidence of cytokine profiles and their involvement in the development of T helper 1 cell responses, SNPs of the promoter region of the IL-10 gene were also analyzed in patients with PBC and controls [53,62,63]. Data from Italian and Japanese series demonstrated that both groups presented a higher prevalence of the -1082G/G genotype [63]. Such association was not confirmed in 77 Chinese patients with PBC [61,62].…”