Susceptibility to relapsing-progressive multiple sclerosis is associated with inheritance of genes linked to the variable region of the TcR β locus: Use of affected family-based controls

Abstract

We tested the hypothesis that susceptibility to relapsing-progressive (RP) (but not to relapsing-remitting [RR]) multiple sclerosis (MS) is associated with a gene linked to the TcR β-chain variable region delimited by the Vβ8-BamHI and Vβ11-BamHI RFLP alleles in DRw15+ MS patients, using a contingency-table test of patient data and affected family-based controls. Control alleles and haplotypes were composed of parental marker alleles and haplotypes not transmitted to the affected child, in 90 simplex and 31 multiplex families from British Columbia. A total of 6,164 alleles at 11 loci were segregated through families of probands with RP MS or RR MS. The Vβ8- Vβ11 subhaplotype frequencies in the DRw15+ RP MS (but not RR Ms) patients differed from control frequencies, because of an increase of the 2-1 subhaplotype (P = .02). Vβ8-BamHI and Vβ11-BamHI allele frequencies (P = .05 and .009, respectively) in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies. The Vβ1-Vβ8 subhaplotype frequencies in the DRw15- RP MS (but not RR MS) patients differed from control frequencies (P = .03), with a significantly increased frequency of the 1-1 subhaplotype (P = .01; RR = 7.1) in RP MS versus RR MS patients. Susceptibility to RP MS is associated both with a recessive inheritance of a gene linked to the 3' (Vβ11) end of the 2-1 subhaplotype defined by the Vβ8-BamHI and Vβ11- BamHI alleles in DRw15+ patients and with a gene, located on the 1-1 subhaplotype, defined by the Vβ1-TaqI and Vβ8-MspI alleles of the TcR β- chain complex in DRw15- patients.