PMID- 20593013
OWN - NLM
STAT- MEDLINE
DCOM- 20100901
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 6
DP  - 2010 Jun 25
TI  - A major histocompatibility Class I locus contributes to multiple sclerosis 
      susceptibility independently from HLA-DRB1*15:01.
PG  - e11296
LID - 10.1371/journal.pone.0011296 [doi]
LID - e11296
AB  - BACKGROUND: In Northern European descended populations, genetic susceptibility 
      for multiple sclerosis (MS) is associated with alleles of the human leukocyte 
      antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex 
      (MHC) genes contribute to MS susceptibility is controversial. 
      METHODOLOGY/PRINCIPAL FINDINGS: A case control analysis was performed using 958 
      single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two 
      independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 
      controls and the replication dataset was composed of 1,343 cases and 1,379 
      controls. The most significantly MS-associated SNP in the discovery dataset was 
      rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS 
      susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for 
      the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed 
      adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple 
      comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III 
      regions were significantly associated with MS susceptibility in both datasets 
      using the Cochran Armitage trend test. The discovery and replication datasets 
      were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. 
      Association tests showed that 48 of the 52 replicated SNPs retained significant 
      associations with MS susceptibility independently of the HLA-DRB1*15:01 as 
      defined by the tagging SNP. 20 Class I SNPs were associated with MS 
      susceptibility with p-values < or = 1 x 10(-8). The most significantly associated 
      SNP was rs4959039, a SNP in the downstream un-translated region of the 
      non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) 
      and is in linkage disequilibrium with several nearby SNPs. Logistic regression 
      modeling showed that this SNP's contribution to MS susceptibility was independent 
      of the Class II and Class III SNPs identified in this screen. CONCLUSIONS: A MHC 
      Class I locus contributes to MS susceptibility independently of the 
      HLA-DRB1*15:01 haplotype.
FAU - Cree, Bruce A C
AU  - Cree BA
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      California, United States of America. bruce.cree@ucsf.edu
FAU - Rioux, John D
AU  - Rioux JD
FAU - McCauley, Jacob L
AU  - McCauley JL
FAU - Gourraud, Pierre-Antoine F D
AU  - Gourraud PA
FAU - Goyette, Philippe
AU  - Goyette P
FAU - McElroy, Joseph
AU  - McElroy J
FAU - De Jager, Philip
AU  - De Jager P
FAU - Santaniello, Adam
AU  - Santaniello A
FAU - Vyse, Timothy J
AU  - Vyse TJ
FAU - Gregersen, Peter K
AU  - Gregersen PK
FAU - Mirel, Daniel
AU  - Mirel D
FAU - Hafler, David A
AU  - Hafler DA
FAU - Haines, Jonathan L
AU  - Haines JL
FAU - Pericak-Vance, Margaret A
AU  - Pericak-Vance MA
FAU - Compston, Alastair
AU  - Compston A
FAU - Sawcer, Stephen J
AU  - Sawcer SJ
FAU - Oksenberg, Jorge R
AU  - Oksenberg JR
FAU - Hauser, Stephen L
AU  - Hauser SL
CN  - IMAGEN
CN  - IMSGC
LA  - eng
GR  - K23 NS048869/NS/NINDS NIH HHS/United States
GR  - R01 NS049477/NS/NINDS NIH HHS/United States
GR  - 068545/Z/02/WT_/Wellcome Trust/United Kingdom
GR  - AI067152/AI/NIAID NIH HHS/United States
GR  - NS21799/NS/NINDS NIH HHS/United States
GR  - G0000934/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - U54 RR020278/RR/NCRR NIH HHS/United States
GR  - U19 AI067152/AI/NIAID NIH HHS/United States
GR  - R01 NS046297/NS/NINDS NIH HHS/United States
GR  - R01NS049477/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100625
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Case-Control Studies
MH  - *Genetic Predisposition to Disease
MH  - HLA-DR Antigens/*genetics
MH  - HLA-DRB1 Chains
MH  - Haplotypes
MH  - Histocompatibility Antigens Class I/*genetics
MH  - Humans
MH  - Linkage Disequilibrium
MH  - Logistic Models
MH  - Multiple Sclerosis/genetics/*immunology
MH  - Polymorphism, Single Nucleotide
PMC - PMC2892470
COIS- Competing Interests: The authors have declared that no competing interests exist.
FIR - Rioux, John D
IR  - Rioux JD
FIR - Goyette, Philippe
IR  - Goyette P
FIR - Vyse, Timothy J
IR  - Vyse TJ
FIR - Hammarstrom, Lennart
IR  - Hammarstrom L
FIR - Fernando, Michelle M A
IR  - Fernando MM
FIR - Green, Todd
IR  - Green T
FIR - De Jager, Philip L
IR  - De Jager PL
FIR - Foisy, Sylvain
IR  - Foisy S
FIR - Wang, Joanne
IR  - Wang J
FIR - de Bakker, Paul I W
IR  - de Bakker PI
FIR - Leslie, Stephen
IR  - Leslie S
FIR - McVean, Gilean
IR  - McVean G
FIR - Padyukov, Leonid
IR  - Padyukov L
FIR - Alfredsson, Lars
IR  - Alfredsson L
FIR - Annese, Vito
IR  - Annese V
FIR - Hafler, David A
IR  - Hafler DA
FIR - Pan-Hammarstrom, Qiang
IR  - Pan-Hammarstrom Q
FIR - Matell, Ritva
IR  - Matell R
FIR - Sawcer, Stephen J
IR  - Sawcer SJ
FIR - Compston, Alastair D
IR  - Compston AD
FIR - Cree, Bruce A C
IR  - Cree BA
FIR - Mirel, Daniel B
IR  - Mirel DB
FIR - Daly, Mark J
IR  - Daly MJ
FIR - Behrens, Tim W
IR  - Behrens TW
FIR - Klareskog, Lars
IR  - Klareskog L
FIR - Gregersen, Peter K
IR  - Gregersen PK
FIR - Oksenberg, Jorge R
IR  - Oksenberg JR
FIR - Hauser, Stephen L
IR  - Hauser SL
FIR - Sawcer, S
IR  - Sawcer S
FIR - Ban, M
IR  - Ban M
FIR - Compston, A
IR  - Compston A
FIR - Oksenberg, J R
IR  - Oksenberg JR
FIR - Cree, B
IR  - Cree B
FIR - De Jager, P L
IR  - De Jager PL
FIR - Weiner, H L
IR  - Weiner HL
FIR - Hafler, D A
IR  - Hafler DA
FIR - Ivinson, A J
IR  - Ivinson AJ
FIR - Hafler, D A
IR  - Hafler DA
FIR - Gabriel, S B
IR  - Gabriel SB
FIR - Mirel, D B
IR  - Mirel DB
FIR - Gregory, S G
IR  - Gregory SG
FIR - Pericak-Vance, M A
IR  - Pericak-Vance MA
FIR - Daly, M J
IR  - Daly MJ
FIR - de Bakker, P I W
IR  - de Bakker PI
FIR - De Jager, P L
IR  - De Jager PL
FIR - Maier, L M
IR  - Maier LM
FIR - Barcellos, L F
IR  - Barcellos LF
FIR - Oksenberg, J R
IR  - Oksenberg JR
FIR - Sawcer, S
IR  - Sawcer S
FIR - Pericak-Vance, M A
IR  - Pericak-Vance MA
FIR - McCauley, J L
IR  - McCauley JL
FIR - Haines, J L
IR  - Haines JL
FIR - Hiller, Jordan
IR  - Hiller J
EDAT- 2010/07/02 06:00
MHDA- 2010/09/02 06:00
PMCR- 2010/06/25
CRDT- 2010/07/02 06:00
PHST- 2010/03/12 00:00 [received]
PHST- 2010/06/04 00:00 [accepted]
PHST- 2010/07/02 06:00 [entrez]
PHST- 2010/07/02 06:00 [pubmed]
PHST- 2010/09/02 06:00 [medline]
PHST- 2010/06/25 00:00 [pmc-release]
AID - 10-PONE-RA-16989R1 [pii]
AID - 10.1371/journal.pone.0011296 [doi]
PST - epublish
SO  - PLoS One. 2010 Jun 25;5(6):e11296. doi: 10.1371/journal.pone.0011296.