TY - JOUR
T1 - Interferon gamma allelic variants
T2 - Sex-biased multiple sclerosis susceptibility and gene expression
AU - Kantarci, Orhun H.
AU - Hebrink, David D.
AU - Schaefer-Klein, Janet
AU - Sun, Yulong
AU - Achenbach, Sara
AU - Atkinson, Elizabeth J.
AU - Heggarty, Shirley
AU - Cotleur, Anne C.
AU - De Andrade, Mariza
AU - Vandenbroeck, Koen
AU - Pelfrey, Clara M.
AU - Weinshenker, Brian G.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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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U2 - 10.1001/archneurol.2007.66
DO - 10.1001/archneurol.2007.66
M3 - Article
C2 - 18332247
AN - SCOPUS:40849136064
SN - 0003-9942
VL - 65
SP - 349
EP - 357
JO - Archives of neurology
JF - Archives of neurology
IS - 3
ER -