FULL PAPER IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis OH Kantarci 1,9 , A Goris 2,9 , DD Hebrink 1 , S Heggarty 3 , S Cunningham 3 , I Alloza 3 , EJ Atkinson 4 , M de Andrade 4 , CT McMurray 5 , CA Graham 6 , SA Hawkins 7 , A Billiau 2 , B Dubois 8 , BG Weinshenker 1 and K Vandenbroeck 3 1 Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA; 2 Rega Institute for Medical Research, University of Leuven, Belgium; 3 Applied Genomics Group, School of Pharmacy, Queen’s University of Belfast, Belfast, UK; 4 Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA; 5 Departments of Pharmacology, Biochemistry and Molecular Biology and Molecular Neuroscience Program, Mayo Clinic and Foundation, Rochester, MN, USA; 6 Northern Ireland Regional Molecular Genetics Laboratory, Belfast City Hospital Trust, UK; 7 Department of Neurology, Royal Victoria Hospital, Belfast, UK; 8 Department of Neurology, University of Leuven, Belgium Interferon-gamma (IFNg) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNg expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1(761)*CA n ], a single nucleotide polymorphism 3 0 of IFNG [3 0 (325)*G-A] and three flanking microsatellite markers spanning a 118 kb region around IFNG. Men carriers of the 3 0 (325)*A allele have increased susceptibility to MS compared to noncarriers in the USA (P ¼ 0.044; OR: 2.58, 95% CI: 0.97–8.08) and Northern Ireland (P ¼ 0.019; OR: 2.37, 95% CI: 1.10–5.13). There is a nonsignificant trend in the same direction in Belgian men (P ¼ 0.299; OR: 1.50, 95% CI: 0.71–3.26). Men carriers of I1(761)*CA 13 , which is in strong linkage disequilibrium with the 3 0 (325)*A, have increased susceptibility (P ¼ 0.050; OR: 2.22, 95% CI: 0.98–5.40), while men carriers of I1(761)*CA 12 have decreased susceptibility (P ¼ 0.022; OR: 0.46, 95% CI: 0.23–0.90) to MS in the USA. Similar associations were reported in Sardinia between the I1(761)*CA 12 allele and reduced risk of MS in men. Flanking markers were not associated with MS susceptibility. Polymorphisms of IFNG may contribute to differences in susceptibility to MS between men and women. Genes and Immunity (2005) 6, 153–161. doi:10.1038/sj.gene.6364164 Published online 27 January 2005 Keywords: multiple sclerosis; gender; interferon gamma (IFNG); polymorphisms; association Introduction Multiple sclerosis (MS) is a complex disease with genetic and environmental influences on susceptibility 1,2 and possibly on the course of disease. 3 Most susceptibility loci, except perhaps the major histocompatibility com- plex, contribute only a small effect. 4–8 Association studies are powerful methods to uncover relatively small effects of allelic variants on complex traits. 9 Interferon-gamma (IFNg) stimulates Th-1 clonal expansion and inhibits Th-2 expansion. The balance between Th-1 and Th-2 CD4 cells is relevant to autoimmunity and to MS. 10,11 IFNg expression is increased in experimental allergic encephalomyelitis (EAE) 12 and parallels disease severity. 13 However, it is unclear whether the increased IFNg expression is a deleterious or a disease limiting response in EAE, as IFNg receptor knockout mice are more susceptible to EAE than wild-type mice. 14,15 Transgenic mice over- expressing IFNg in the central nervous system under the control of an oligodendrocyte-specific promoter develop extensive primary demyelination compared to wild-type mice. 16,17 IFNg may exert deleterious effects directly on myelinating cells and also through activation of macro- phages and microglia. 18 IFNg also induces dendritic retraction and inhibits synapse formation. 19 IFNg expression increases in the 2 weeks preceding attacks of MS. 20,21 Low levels of IFNg expression by lymphocytes at the initiation of treatment with IFNb predict a favorable response to treatment. 22 Treatment with exogenous IFNg is deleterious to patients with MS. 23 However, as is the case in EAE, whether endogenous IFNg expression represents a deleterious or a disease limiting effect in MS is unknown. Genetic variants that affect expression or function of IFNg might favorably or unfavorably influence the susceptibility to and course and severity of MS. Received 9 August 2004; revised 11 November 2004; accepted 11 November 2004; published online 27 January 2005 Correspondence: Dr BG Weinshenker, Department of Neurology, Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905, USA. E-mail: weinb@mayo.edu 9 These two authors contributed equally to this work. Genes and Immunity (2005) 6, 153–161 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene