HLA and T-cell receptor polymorphisms in Belgian multiple sclerosis patients: No evidence for disease association with the T-cell receptor

Vandevyver, Caroline; Buyse, Inge M.; Philippaerts, L; Ghabanbasani, Z; Medaer, R.; Carton, Herwig; Cassiman, Jean‐Jacques; Raus, Jef

doi:10.1016/0165-5728(94)90158-9

Cited by 23 publications

(12 citation statements)

References 45 publications

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“…The importance of the TR in immune responses make them key candidates for searches to identify risk conferring alleles for immune disorders such as rheumatoid arthritis (RA), multiple sclerosis (MS), atopy, asthma, and insulin-dependent diabetes, among others (Fukazawa et al 2000;Hall et al 1997;Hockertz et al 1998;Moffatt et al 1994Moffatt et al , 1997Oksenberg et al 1988;Roschmann et al 1993;Vandevyver et al 1994;Wei et al 1995). Common human diseases are thought to be associated with common variants located in multiple genes with each variant contributing modestly to genetic risk .…”

Section: Introductionmentioning

confidence: 97%

Sequence diversity, natural selection and linkage disequilibrium in the human T cell receptor alpha/delta locus

et al. 2006

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T cell receptors (TR), through their interaction with the major histocompatibility complex, play a central role in immune responsiveness and potentially immune-related disorders. We resequenced all 57 variable (V) genes in the human T cell receptor alpha and delta (TRA/TRD) locus in 40 individuals of Northern European, Mexican, African-American and Chinese descent. Two hundred and eighty-four single nucleotide polymorphisms (SNPs) were identified. The distribution of SNPs between V genes was heterogeneous, with an average of five SNPs per gene and a range of zero to 15. We describe the patterns of linkage disequilibrium for these newly discovered SNPs and compare these patterns with other emerging large-scale datasets (e.g. Perlegen and HapMap projects) to place our findings into a framework for future analysis of genotype-phenotype associations across this locus. Furthermore, we explore signatures of natural selection across V genes. We find evidence of strong directional selection at this locus as evidenced by unusually high values of Fst.

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Section: Introductionmentioning

confidence: 97%

Sequence diversity, natural selection and linkage disequilibrium in the human T cell receptor alpha/delta locus

et al. 2006

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“…37 Subsequent association studies investigating the role of TCR alpha polymorphisms in Canadian, Swedish, Belgian and Northern Irish populations with equivalent or larger sample sizes compared with those above were unable to replicate these findings. 34,35,39,40 Also, in two of these studies, no interaction between HLA-DR2 and TRA genotypes was observed. 35,39 Additionally, Hillert et al…”

Section: T-cell Receptorsmentioning

confidence: 74%

“…34,35,39,40 Also, in two of these studies, no interaction between HLA-DR2 and TRA genotypes was observed. 35,39 Additionally, Hillert et al…”

Section: T-cell Receptorsmentioning

confidence: 74%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence.

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“…Similar to the TCR linkage analysis results, many other research groups have failed to confirm a significant association. [16][17][18][19][20][21] The reasons for these discrepant results are many and may include population stratification, small sample sizes, clinical heterogeneity within the MS patient sample, informativity of the selected markers or simply the reporting of false-positive results. 22 The low reproducibility of positive genetic association studies has drawn appropriate comment.…”

Section: Introductionmentioning

confidence: 99%

TCR β polymorphisms and multiple sclerosis

et al. 2004

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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.

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HLA and T-cell receptor polymorphisms in Belgian multiple sclerosis patients: No evidence for disease association with the T-cell receptor

Cited by 23 publications

References 45 publications

Sequence diversity, natural selection and linkage disequilibrium in the human T cell receptor alpha/delta locus

Sequence diversity, natural selection and linkage disequilibrium in the human T cell receptor alpha/delta locus

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

TCR β polymorphisms and multiple sclerosis

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