Inheritance mode of multiple sclerosis: the effect of HLA class II alleles is stronger than additive.

We previously identified on chromosome 6 an interval of 51 kb as the most likely interval in the HLA region for a disease-susceptibility locus for multiple sclerosis (MS). The interval was located between markers G511525 and D6S1666 and identified by the haplotype sharing statistic (HSS). The study comprised 124 patients with ancestry within the northeastern part of The Netherlands. Haplotype clustering indicated that two different ancestral haplotypes likely include a polymorphism involved in susceptibility to MS. To investigate the dominance characteristics of the MS susceptibility locus in the HLA class II region, we reanalyzed our data, performing genotype association analyses for both marker loci separately and for the two-locus haplotype. The two-locus genotype association analysis showed that in individuals who carry only one of the risk haplotypes the risk for MS is moderately increased (odds ratio (OR) 2.82; 95% confidence interval (CI) 1.50-5.31). However, in individuals carrying two risk haplotypes the risk for MS is highly increased compared with individuals who carry no risk haplotypes (OR 37.00; 95% CI 8.31-164.74). This susceptibility locus for MS seems to follow an intermediate mode of inheritance. Fitting additive, multiplicative and third power risk models to the data, the effect appears to be significantly stronger than additive.