SUSCEPTIBILITY FOR MULTIPLE-SCLEROSIS IS DETERMINED, IN PART, BY INHERITANCE OF A 175-KB REGION OF THE TCR V-BETA-CHAIN LOCUS AND HLA CLASS-II GENES

Genetic makeup thought to affect susceptibility to multiple sclerosis (MS) and current evidence suggests that multiple genes may be involved. We have mapped a potential susceptibility gene or genes in the germ-line T cell receptor (TcR) Vbeta region of multiple sclerosis (MS) patients. Six restriction fragment length polymorphisms (RFLPs) spanning approximately 600 kb of the TcR Vbeta region were used to define TcR haplotypes in 197 Caucasian controls and 83 Caucasian MS patients in the chronic progressive stage of the disease. The distribution of TcR subhaplotype frequencies was significantly different only in the approx. 175-kb region between RFLPs defined by Vbeta8.1 and Vbeta11. Stratification of the MS patients into HLA-DR2+ (n = 51) and HLA-DR2- (n = 32) populations demonstrated that the subhaplotype frequencies differed from the control population significantly only in the HLA-DR2+ (corrected P = 0.00007) and not in the HLA-DR2- (corrected P = 0.46) population. Subhaplotypes which are rare in the normal population are overrepresented in the HLA-DR2+ MS patient population and confer a relative risk of 4.06. These results indicate the existence of an MS susceptibility gene within the TcR Vbeta region, and provide new evidence for gene complementation between a HLA class II gene and TcR Vbeta gene(s) in conferring susceptibility to MS.