TCR β polymorphisms and multiple sclerosis

Abstract

A total of 267 families with two or more siblings with multiple sclerosis (MS) were genotyped with 14 restriction fragment length polymorphisms at the TCR b locus. A nonparametric linkage analysis of the data showed no evidence for linkage to this locus (mlod ¼ 0.11). No significant allelic or haplotype transmissions were observed in the total sample of 565 patients. After stratification for the presence of HLA DRB1*15, an association was observed between the BV25S1*1-BV26S1*1-BV2S1*1 haplotype and MS (P ¼ 0.00089). This was not significant upon correction for multiple comparisons. It was also not significant when the haplotype frequency in affected individuals was compared to a normal control sample (P ¼ 0.77). Furthermore, the associated haplotype was followed-up in an independent sample of 97 nuclear families with a single DRB1*15-positive child with MS. The BV25S1*1-BV26S1*1-BV2S1*1 haplotype did not show significant evidence for transmission distortion but the same trend was seen (P ¼ 0.21). There were no significant associations observed in the DRB1*15-negative patients and no detectable difference was seen in the DRB1*15-positive BV25S1*1-BV26S1*1-BV2S1*1 association when comparing different subgroups based on clinical course of MS. These results show no evidence for linkage and fail to establish an association between MS susceptibility and the TCR b locus.

Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis

“…Dyment et al 43 observed an over transmission of the TCR beta haplotype, BV25S1*1-BV26S1*1-BV2S1*1, after stratification for HLA-DRB1*1501, although this association was not confirmed in a replication cohort. 43 The MHC class II activator gene, CIITA, has also recently been shown to increase risk in MS families positive for HLA-DRB1*1501 (Bronson et al…”

“…29 Although a role for T cells in MS seems indisputable, no consistent and replicable genetic associations have been made between polymorphisms at T-cell receptor (TCR) loci and MS, despite suggestive links to both TCR beta and alpha genes. [30][31][32][33][34][35][36][37][38][39][40][41][42][43] A possible explanation for the observed inconsistency between studies investigating TCR gene loci and MS could be a lack of power to discover associations, because of small sample sizes and unrepresentative marker coverage of the TCR regions investigated. Given these limitations, it is reasonable to conclude that, although no strong associations have been identified within the TCR loci, these regions cannot be unequivocally ruled out on the basis of previous studies alone.…”

Genetic and Molecular Approaches to the Immunopathogenesis of Multiple Sclerosis: An Update

“…Polymorphisms of the TCR variable (V) genes have been extensively studied with conflicting results (reviewed in [181]). A more recent study of 267 families with two or more siblings with MS did not demonstrate any significant evidence for linkage or association with germline genes at the TCR V locus [182].…”

Polymorphism in the third intron of the interferonγ gene is associated with susceptibility to multiple sclerosis

“…Recently, much research has been conducted in the field of molecular biology on the genetic predisposition to MS via examinations of gene polymorphisms. Some genes of interest include the human leukocyte antigen (HLA) gene, the T cells receptor (TCR) gene (Dyment et al, 2004), the tumor necrosis factor (TNF) (Fernandez-Arquero et al, 1999) gene, the vitamin D receptor (VDR) gene (Fukazawa et al, 1999;Niino et al, 2000), the female hormone estrogen receptor (ER) (Savettieri et al, 2002), and the low molecular weight polypeptide (LMP) gene (Liblau et al, 1993;Omran et al, 2013). However, many of the early association studies cannot be duplicated due to differences in disease etiology and clinical methodologies.…”