Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases.
The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.
Research Center, Université de Montréal and Montreal Heart Institute, Montreal, QC, Canada.
Rioux
John D
JD
Goyette
Philippe
P
Vyse
Timothy J
TJ
Hammarström
Lennart
L
Fernando
Michelle M A
MM
Green
Todd
T
De Jager
Philip L
PL
Foisy
Sylvain
S
Wang
Joanne
J
de Bakker
Paul I W
PI
Leslie
Stephen
S
McVean
Gilean
G
Padyukov
Leonid
L
Alfredsson
Lars
L
Annese
Vito
V
Hafler
David A
DA
Pan-Hammarström
Qiang
Q
Matell
Ritva
R
Sawcer
Stephen J
SJ
Compston
Alastair D
AD
Cree
Bruce A C
BA
Mirel
Daniel B
DB
Daly
Mark J
MJ
Behrens
Tim W
TW
Klareskog
Lars
L
Gregersen
Peter K
PK
Oksenberg
Jorge R
JR
Hauser
Stephen L
SL
D002874:Chromosome Mapping; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000276:immunology*
D006680:HLA Antigens