Strong Linkage Disequilibrium between HLA—Dw2 and BfS in Multiple Sclerosis and in the Normal Population

Abstract

An increased frequency of the S allele of Properdin factor B (BfS) was found amongst 162 patients with multiple sclerosis (MS) compared with 470 normal controls. This increase was shown to be due to a strong linkage disequilibrium (LD) between BfS and HLA—Dw2 in 77 patients typed for both systems (Δ= 3.84%, P= .0002). The same LD was demonstrated amongst 100 normal controls (Δ= 2.24%, P= .0049) and 31 patients with idiopathic demyelination of the peripheral nervous system (IDPN). A total of 70 haplotypes with HLA‐Dw2 were encountered (40 MS, seven IDPN and 23 normal controls) and all contained BfS. In the MS patient group, a much weaker association was noted between BfS and HLA—B7 suggesting either that the Bf locus is much closer to the HLA—D than the HLA—B locus or (and) that HLA‐D and Bf products selectively interact (perhaps on the surface of B lymphocytes) with evolutionary advantage or disadvantage resulting from certain allelic combinations. Strong associations between BfS1 and HLA—Bw21 (P= .0000) and BfF1 and HLA—B18 (P= .0001), both previously reported, were confirmed in the current study. No increase in the frequency of a glyoxalase (GLO) allele was found amongst the MS patients and no LD was encountered between HLA—Dw2 and a GLO allele. The possibility that the HLA—Dw2, BfS disequilibrium has resulted from a selective advantage conferred on the general community but at the expense of increasing susceptibility to MS should be considered.

HLA and multiple sclerosis: population and families study

“…The world distribution of the disease (for general review see Acheson 1977) and the special prevalence in Scandinavian countries with a relative scarcity in South Europe were related to latitude and to the decreasing incidence of the haplotype A3, B7, DR2 along a North-South axis tracing the "Viking" migrations from the 8th to 11th centuries. Moreover, HLA-DR2 was claimed to be more frequent in rapidly progressive MS (Acheson 1977, Walker et al 1982 although the severity of the disease seemed to be related to B8, DR3 (Madigand 1980) but also to Bf S (Stewart et al 1979, Fielder et al 1981. This impairment was related to a decrease of interferon a synthesis in DR2 positive patients .…”