Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients

The proinflammatory cytokine interferon (IFN)-gamma has been shown to influence the course of multiple sclerosis (MS). The IFN-gamma (IFNG) contains a multiallelic dinucleotide repeat in intron 1. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-gamma mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron 1 genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octle. Comparison of IFN-gamma mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron 1 dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-gamma mRNA expression in vivo.