A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.
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.


RESULTS
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.
Cree
Bruce A C
BA
Department of Neurology, University of California San Francisco, San Francisco, California, United States of America. bruce.cree@ucsf.edu
Rioux
John D
JD
McCauley
Jacob L
JL
Gourraud
Pierre-Antoine F D
PA
Goyette
Philippe
P
McElroy
Joseph
J
De Jager
Philip
P
Santaniello
Adam
A
Vyse
Timothy J
TJ
Gregersen
Peter K
PK
Mirel
Daniel
D
Hafler
David A
DA
Haines
Jonathan L
JL
Pericak-Vance
Margaret A
MA
Compston
Alastair
A
Sawcer
Stephen J
SJ
Oksenberg
Jorge R
JR
Hauser
Stephen L
SL
D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I