Analysis of an IFN-gamma gene (IFNG) polymorphism in multiple sclerosis inEurope: Effect of population structure on association with disease

An intronic dinucleotide polymorphism in the IFN-gamma gene (IFNG) was used as a marker for testing association with multiple sclerosis FIS). Disease association was analyzed in case-control sets sampled from four geographica lly separate European populations (Germany, Northern Italy, Sardinia, and S weden). Only in the Swedish was a weak disease association of the IFNG alle le pattern found, mainly due to a higher frequency of IFNG allele I1 in MS patients. Na evidence for association was found in the German or Northern I talian populations. These results contrast with the situation in Sardinia, We have recently reported transmission disequilibrium of IFNG allele I2 in Sardinian MS siblings not carrying the predisposing DRB1*03 or *04 alleles (Ann, Neurol, 44, 841-842, 1998), Further analysis now shows that I2 is sig nificantly more often transmitted to DRB1*03(-)/*04(-) males, than to DRB1* 03(-)/*04(-). females. The odds ratio (OR) for IFNG-associated susceptibili ty to MS in the total Sardinian DRB1*03(-)/*04(-) group was 1.88 for I2 het erozygotes but amounted to 8.235 for I2 homozygotes, suggestive of a recess ive mode of inheritance. Score test-based statistics pointed to an I2 allel e dosage effect acting in susceptibility. Comparison of the IFNG allele fre quencies in seven European populations (Northern Finnish, Southern Finnish, Swedish, Danish, German, Italian, and Sardinian) revealed a highly differe nt distribution pattern. We introduced latitude as a score variable in orde r to test for trend in binomial proportions, This test statistic showed tha t for both most common alleles, I1 and I2 (compiled allele frequency about 85%), a significant opposite north-to-south trend is seen throughout Europe . This effect is primarily due to the extreme values found in the outlier p opulations of Finland and Sardinia. Our findings are discussed with respect to recent literature pertinent to the role of the IFNG chromosome region i n autoimmune diseases.