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.
John D
JD
Rioux
Philippe
P
Goyette
Timothy J
TJ
Vyse
Lennart
L
Hammarström
Michelle M A
MM
Fernando
Todd
T
Green
Philip L
PL
De Jager
Sylvain
S
Foisy
Joanne
J
Wang
Paul I W
PI
de Bakker
Stephen
S
Leslie
Gilean
G
McVean
Leonid
L
Padyukov
Lars
L
Alfredsson
Vito
V
Annese
David A
DA
Hafler
Qiang
Q
Pan-Hammarström
Ritva
R
Matell
Stephen J
SJ
Sawcer
Alastair D
AD
Compston
Bruce A C
BA
Cree
Daniel B
DB
Mirel
Mark J
MJ
Daly
Tim W
TW
Behrens
Lars
L
Klareskog
Peter K
PK
Gregersen
Jorge R
JR
Oksenberg
Stephen L
SL
Hauser
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