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  • Title: Interferon gamma allelic variants: sex-biased multiple sclerosis susceptibility and gene expression.
    Author: Kantarci OH, Hebrink DD, Schaefer-Klein J, Sun Y, Achenbach S, Atkinson EJ, Heggarty S, Cotleur AC, de Andrade M, Vandenbroeck K, Pelfrey CM, Weinshenker BG.
    Journal: Arch Neurol; 2008 Mar; 65(3):349-57. PubMed ID: 18332247.
    Abstract:
    BACKGROUND: Interferon (IFN) gamma (IFNG) allelic variants are associated with susceptibility to multiple sclerosis (MS) in men but not in women. OBJECTIVES: 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. DESIGN: Genotype case-control study, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay expression analyses for IFN gamma. SETTING: Three independently ascertained populations from the Mayo Clinic, Rochester, Minnesota, Queen's University of Belfast, Belfast, Ireland, and University of Leuven, Leuven, Belgium. PATIENTS: 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. INTERVENTIONS: Twenty markers were genotyped over the 120-kilobase region harboring IFNG and the interleukin 26 gene (IL26). MAIN OUTCOME MEASURES: 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.
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