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Sex-Biased Multiple Sclerosis Susceptibility and Gene Expression

Orhun H. Kantarci, MD; David D. Hebrink, BA; Janet Schaefer-Klein, BS; Yulong Sun, PhD; Sara Achenbach, MS; Elizabeth J. Atkinson, MS; Shirley Heggarty, PhD; Anne C. Cotleur, MS; Mariza de Andrade, PhD; Koen Vandenbroeck, PhD; Clara M. Pelfrey, PhD; Brian G. Weinshenker, MD

Arch Neurol. 2008;65(3):349-357.

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.

Author Affiliations: Department of Neurology, Mayo Clinic College of Medicine (Drs Kantarci, Sun, and Weinshenker, Mr Hebrink, and Ms Schaefer-Klein), and Department of Health Sciences Research, Mayo Clinic and Foundation (Mss Achenbach and Atkinson and Dr de Andrade), Rochester, Minnesota; Applied Genomics Research Group, School of Pharmacy, Queen's University of Belfast, Belfast, Ireland (Drs Heggarty and Vandenbroeck); and Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio (Ms Cotleur and Dr Pelfrey).

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