Identification of HAVCR1 gene haplotypes associated with mRNA expression levels and susceptibility to autoimmune diseases

Abstract

Human HAVCR1 gene maps on 5q33.2, a region linked with susceptibility to allergic and autoimmune diseases. The aims of the present study were to define the haplotypes of HAVCR1 gene taking into account both HapMap Project SNP haplotypes and exon 4 variants, to investigate a possible relationship between these haplotypes and mRNA expression levels, and to assess whether HAVCR1 gene is involved in susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Genotyping of three ins/del variants in the exon 4 was performed by fragment length analysis. Five tag SNPs genotypes and mRNA levels were determined using TaqMan assays. We defined four major haplotypes in our population: the two major haplotypes (named haplotypes A and B) bear both the 5383_5397del variant and the two most common SNP sets found in the CEU population. Quantification analysis revealed that genotype B/B had the highest median of mRNA expression levels (vs. BX + XX, p < 0.0001). Additionally, frequency of the genotype BB was significantly higher in RA patients than in controls (12.3 vs. 5.9% in controls, p = 0.0046, p (c) = 0.014, OR = 2.23, 95% CI 1.23-4.10). Our results support a relationship between HAVCR1 haplotypes and mRNA expression levels, and suggest an association of this gene with autoimmune diseases.

Binding of Hepatitis A Virus to Its Cellular Receptor 1 Inhibits T-Regulatory Cell Functions in Humans

“…However, the mechanism by which HAV modulates autoimmune diseases has not been explored in detail. In man, HAVCR1 has been implicated in susceptibility to rheumatoid arthritis 9, 27 . In mouse, Treg do not express mHavcr1 but it is constitutively expressed in dendritic cells and indirectly modulates Treg-function 28 .…”

“…The mechanism by which HAV blocks Tregs without enhancing immune-mediated tissue damage or preventing viral growth is unclear. To enter the cell, HAV interacts with its cellular receptor 1, HAVCR1 6, 7 , a significant allergy and autoimmunity determinant in man 8, 9 . HAVCR1 is expressed in T-cells where it functions as a phosphatidylserine (PtdSer) receptor and T-cell costimulatory molecule 8 , which suggests that the HAV-HAVCR1 interaction on T-cells is responsible for the long-lasting effect of HAV infection in the immune system.…”

HAVCR1 Gene Haplotypes and Infection by Different Viral Hepatitis C Virus Genotypes

“…The HAVCR1 gene is highly polymorphic in promoter regions as well as in coding regions, with single nucleotide polymorphisms (SNPs) and insertion/deletion (ins/del) variants located throughout the gene and, more specifically, in the exon 4 encoding the functional mucin domain. In a previous study, we reported the 4 most common HAVCR1 gene haplotypes in our population; one of them, haplotype B, was associated with higher mRNA expression levels and susceptibility to rheumatoid arthritis (5). Because of the high degree of variability of this gene, it is possible that the variants associated with HCV infection depend on the population studied.…”

Regulation of T cell trafficking by the T cell immunoglobulin and mucin domain 1 glycoprotein

“…Interestingly, TIM-1 was also proposed to be involved in the development of autoimmune diseases. Polymorphisms in exon 4 or the promoter region are associated with increased susceptibility to rheumatoid arthritis [86][87][88][89]. Furthermore, cerebrospinal fluid mononuclear cells from MS patients express TIM-1 mRNA, particularly during remission, suggesting that TIM-1 may be involved in protective mechanisms during the clinical course of MS, possibly associated with tolerance mechanisms [90].…”