A second major histocompatibility complex susceptibility locus for multiple sclerosis.
OBJECTIVE
Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.


METHODS
Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.


RESULTS
Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)).


CONCLUSIONS
Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.
Yeo
Tai Wai
TW
Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
De Jager
Philip L
PL
Gregory
Simon G
SG
Barcellos
Lisa F
LF
Walton
Amie
A
Goris
An
A
Fenoglio
Chiara
C
Ban
Maria
M
Taylor
Craig J
CJ
Goodman
Reyna S
RS
Walsh
Emily
E
Wolfish
Cara S
CS
Horton
Roger
R
Traherne
James
J
Beck
Stephan
S
Trowsdale
John
J
Caillier
Stacy J
SJ
Ivinson
Adrian J
AJ
Green
Todd
T
Pobywajlo
Susan
S
Lander
Eric S
ES
Pericak-Vance
Margaret A
MA
Haines
Jonathan L
JL
Daly
Mark J
MJ
Oksenberg
Jorge R
JR
Hauser
Stephen L
SL
Compston
Alastair
A
Hafler
David A
DA
Rioux
John D
JD
Sawcer
Stephen
S
D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D006681:HLA-D Antigens / Q000235:genetics; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D006681:HLA-D Antigens