Variation within DNA repair pathway genes and risk of multiple sclerosis.
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system with a prominent genetic component. The primary genetic risk factor is the human leukocyte antigen (HLA)-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has not been elucidated. The authors investigated the relation between variation in DNA repair pathway genes and risk of MS. Single-locus association testing, epistatic tests of interactions, logistic regression modeling, and nonparametric Random Forests analyses were performed by using genotypes from 1,343 MS cases and 1,379 healthy controls of European ancestry. A total of 485 single nucleotide polymorphisms within 72 genes related to DNA repair pathways were investigated, including base excision repair, nucleotide excision repair, and double-strand breaks repair. A single nucleotide polymorphism variant within the general transcription factor IIH, polypeptide 4 gene, GTF2H4, on chromosome 6p21.33 was significantly associated with MS (odds ratio = 0.7, P = 3.5 x 10(-5)) after accounting for multiple testing and was not due to linkage disequilibrium with HLA-DRB1*1501. Although other candidate genes examined here warrant further follow-up studies, collectively, these results derived from a well-powered study do not support a strong role for common variation within DNA repair pathway genes in MS.
Briggs
Farren B S
FB
University of California, Berkeley, 94720, USA.
Goldstein
Benjamin A
BA
McCauley
Jacob L
JL
Zuvich
Rebecca L
RL
De Jager
Philip L
PL
Rioux
John D
JD
Ivinson
Adrian J
AJ
Compston
Alastair
A
Hafler
David A
DA
Hauser
Stephen L
SL
Oksenberg
Jorge R
JR
Sawcer
Stephen J
SJ
Pericak-Vance
Margaret A
MA
Haines
Jonathan L
JL
Barcellos
Lisa F
LF
D004260:DNA Repair / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People