Interferon gamma allelic variants: Sex-biased multiple sclerosis susceptibility and gene expression

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

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalArchives of neurology
Volume65
Issue number3
DOIs
StatePublished - Mar 2008

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

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    Kantarci, O. H., Hebrink, D. D., Schaefer-Klein, J., Sun, Y., Achenbach, S., Atkinson, E. J., Heggarty, S., Cotleur, A. C., De Andrade, M., Vandenbroeck, K., Pelfrey, C. M., & Weinshenker, B. G. (2008). Interferon gamma allelic variants: Sex-biased multiple sclerosis susceptibility and gene expression. Archives of neurology, 65(3), 349-357. https://doi.org/10.1001/archneurol.2007.66