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

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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

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Interferon-gamma
Multiple Sclerosis
Gene Expression
Belgium
Linkage Disequilibrium
Polymerase Chain Reaction
Enzyme-Linked Immunosorbent Assay
Genotype
Sexism
Northern Ireland
Interleukins
Homozygote
Susceptibility
Ireland
Population
Case-Control Studies
Blood Cells
Outcome Assessment (Health Care)
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

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Interferon gamma allelic variants : Sex-biased multiple sclerosis susceptibility and gene expression. / Kantarci, Orhun H; Hebrink, David D.; Schaefer-Klein, Janet; Sun, Yulong; Achenbach, Sara; Atkinson, Elizabeth J.; Heggarty, Shirley; Cotleur, Anne C.; De Andrade, Mariza; Vandenbroeck, Koen; Pelfrey, Clara M.; Weinshenker, Brian G.

In: Archives of Neurology, Vol. 65, No. 3, 03.2008, p. 349-357.

Research output: Contribution to journalArticle

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 2008, 'Interferon gamma allelic variants: Sex-biased multiple sclerosis susceptibility and gene expression', Archives of Neurology, vol. 65, no. 3, pp. 349-357. https://doi.org/10.1001/archneurol.2007.66
Kantarci, Orhun H ; Hebrink, David D. ; Schaefer-Klein, Janet ; Sun, Yulong ; Achenbach, Sara ; Atkinson, Elizabeth J. ; Heggarty, Shirley ; Cotleur, Anne C. ; De Andrade, Mariza ; Vandenbroeck, Koen ; Pelfrey, Clara M. ; Weinshenker, Brian G. / Interferon gamma allelic variants : Sex-biased multiple sclerosis susceptibility and gene expression. In: Archives of Neurology. 2008 ; Vol. 65, No. 3. pp. 349-357.
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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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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

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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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