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.
University of California, Berkeley, 94720, USA.
Farren B S
FB
Briggs
Benjamin A
BA
Goldstein
Jacob L
JL
McCauley
Rebecca L
RL
Zuvich
Philip L
PL
De Jager
John D
JD
Rioux
Adrian J
AJ
Ivinson
Alastair
A
Compston
David A
DA
Hafler
Stephen L
SL
Hauser
Jorge R
JR
Oksenberg
Stephen J
SJ
Sawcer
Margaret A
MA
Pericak-Vance
Jonathan L
JL
Haines
Lisa F
LF
Barcellos
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