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Fine-mapping the genetic association of the major histocompatibility complex in Multiple Sclerosis: HLA and non-HLA effects

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Patsopoulos, NA and Barcellos, LF and Hintzen, RQ and Schaefer, C and van Duijn, CM and Noble, JA and Raj, T and Bernardinelli, L and Booth, D and Comabella, M and Compston, A and D'Alfonso, S and Fontaine, B and Goris, A and Haines, J and Harbo, H and Hauser, S and Hawkins, C and Hemmer, B and Ivinson, A and Lill, C and Martin, R and Martinelli-Boneschi, F and Oturai, A and Palotie, A and Pericak-Vance, M and Saarela, J and Stewart, G and Zipp, F and Scott, RJ and Lechner-Scott, J and Moscato, P and Heard, RN and Mason, D and Griffith, L and Broadley, S and Brown, MA and Slee, M and Foote, SJ and Stankovich, J and Wiley, J and Bahlo, M and Perreau, V and Field, J and Butzkueven, H and Kilpatrick, T and Rubio, J and Marriott, M and Carroll, WM and Kermode, AG and Gourraud, P-A and Stranger, BE and Oksenberg, J and Olsson, T and Taylor, BV and Sawcer, S and Hafler, DA and Carrington, M and De Jager, PL and de Bakker, PIW, Fine-mapping the genetic association of the major histocompatibility complex in Multiple Sclerosis: HLA and non-HLA effects, PLoS Genetics, 9, (11) Article e1003926. ISSN 1553-7404 (2013) [Refereed Article]


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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

DOI: doi:10.1371/journal.pgen.1003926

Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Foote, SJ (Professor Simon Foote)
Author:Stankovich, J (Dr Jim Stankovich)
Author:Taylor, BV (Professor Bruce Taylor)
ID Code:88325
Year Published:2013
Web of Science® Times Cited:66
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-01-29
Last Modified:2014-06-25
Downloads:398 View Download Statistics

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