A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.
Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.
Lincoln
Matthew R
MR
Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.
Montpetit
Alexandre
A
Cader
M Zameel
MZ
Saarela
Janna
J
Dyment
David A
DA
Tiislar
Milvi
M
Ferretti
Vincent
V
Tienari
Pentti J
PJ
Sadovnick
A Dessa
AD
Peltonen
Leena
L
Ebers
George C
GC
Hudson
Thomas J
TJ
D002170:Canada; D005387:Finland; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D009103:Multiple Sclerosis / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II