Dataset Information

TRAIL/TRAIL receptor system and susceptibility to multiple sclerosis.

ABSTRACT: The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p?=?9.8×10(-4), OR?=?1.34; rs4872077, in TRAILR-1 gene, p?=?0.005, OR?=?1.72; and rs1001793 in TRAILR-2 gene, p?=?0.012, OR?=?0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p?=?2.12×10(-5), OR?=?0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS.

SUBMITTER: Lopez-Gomez C

PROVIDER: S-EPMC3140982 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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TRAIL/TRAIL receptor system and susceptibility to multiple sclerosis.

López-Gómez Carlos C Fernández Oscar O García-León Juan Antonio JA Pinto-Medel María Jesús MJ Oliver-Martos Begoña B Ortega-Pinazo Jesús J Suardíaz Margarita M García-Trujillo Lucía L Guijarro-Castro Cristina C Benito-León Julián J Prat Isidro I Varadé Jezabel J Álvarez-Lafuente Roberto R Urcelay Elena E Leyva Laura L

PloS one 20110721 7

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in ...[more]

PMID: 21814551

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Project description:ObjectiveTo explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.BackgroundRecently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort.Design/methodsThe African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational "Be the Match" registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms.ResultsOf the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)-similar to that observed in the WTCCC (OR = 3.25; p<10-168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)-again, similar to the WTCCC (OR = 2.2; p<10-38). Moreover, four African haplotypes were "protective" relative to a neutral reference, to three European CEHs, and also to the five other African CEHs.ConclusionsThe common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were "protective"-perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.

Dataset Information

TRAIL/TRAIL receptor system and susceptibility to multiple sclerosis.

Publications

TRAIL/TRAIL receptor system and susceptibility to multiple sclerosis.

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