Interferon gamma allelic variants: sex-biased multiple sclerosis susceptibility and gene expression.
BACKGROUND
Interferon (IFN) gamma (IFNG) allelic variants are associated with susceptibility to multiple sclerosis (MS) in men but not in women.


OBJECTIVE
To conduct a high-density linkage disequilibrium association study of IFNG and the surrounding region for sex-associated MS susceptibility bias and to evaluate whether IFNG allelic variants associated with MS susceptibility are associated with expression.


METHODS
Genotype case-control study, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay expression analyses for IFN gamma.


METHODS
Three independently ascertained populations from the Mayo Clinic, Rochester, Minnesota, Queen's University of Belfast, Belfast, Ireland, and University of Leuven, Leuven, Belgium.


METHODS
For linkage disequilibrium, 861 patients with MS (293 men and 568 women) and 843 controls (340 men and 503 women) derived from the US (population-based) and the Northern Ireland and Belgium (clinic-based) cohorts were studied. For expression analyses, 50 US patients were selected to enrich for homozygotes and to achieve a balance between men and women.


METHODS
Twenty markers were genotyped over the 120-kilobase region harboring IFNG and the interleukin 26 gene (IL26).


METHODS
Expression of IFN gamma was evaluated by qPCR and enzyme-linked immunosorbent assay in stimulated peripheral blood mononuclear cells.


RESULTS
Multiple markers were associated with MS susceptibility in men but not in women. The sex-specific susceptibility markers, of which rs2069727 was the strongest, were confined to IFNG. Carriers of rs2069727*G had higher expression than noncarriers. The effect of genotype in the qPCR experiments was also evident in men but not in women.


CONCLUSIONS
IFNG is associated with sex bias in MS susceptibility and with expression of IFN gamma in MS. These observations add to a growing body of literature that implicates an interaction between sex and IFN gamma expression in a variety of disease states.
Kantarci
Orhun H
OH
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Hebrink
David D
DD
Schaefer-Klein
Janet
J
Sun
Yulong
Y
Achenbach
Sara
S
Atkinson
Elizabeth J
EJ
Heggarty
Shirley
S
Cotleur
Anne C
AC
de Andrade
Mariza
M
Vandenbroeck
Koen
K
Pelfrey
Clara M
CM
Weinshenker
Brian G
BG
D000483:Alleles; D001530:Belgium / Q000453:epidemiology; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D007494:Ireland / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012727:Sex Characteristics; D014481:United States / Q000453:epidemiology
D007371:Interferon-gamma