An approach to the localization of the susceptibility genes for generalized myasthenia gravis by mapping recombinant ancestral haplotypes

Abstract

The association of HLA A1, B8, and DR3 with generalized myasthenia gravis (GMG) in Caucasoids is well established, but no particular gene has been implicated and there is still no adequate explanation in functional terms. In this study we have taken advantage of sequential genomic markers between B8 and DR3 so as to map the location of susceptibility gene(s) on the A1, B8, DR3 (8.1) ancestral haplotype. By studying 51 patients, we have delineated a region between HLA B and TNF which is shared by 29/29 patients with B8 and DR3, 19/19 patients with B8 but not DR3 and 2/3 patients with DR3 but not B8. The potential importance of this region was confirmed by examining a similar disease induced by D-Penicillamine (D-PenMG) and associated with different HLA class II alleles (DR1 and/or DR7). Among these patients, 7/16 (44%) have B8, often with other markers of 8.1. These results implicate at least two categories of genes in determining susceptibility to MG; one located in the region between HLA B and TNF may be immunoregulatory, whereas the second, located in the class II region, may relate to the inducing factor (e.g., DR1 or DR7 in D-PenMG).

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

“…47 Analysis of SNP haplotypes The disease mutation is introduced in the population on a specific haplotype background. 56 Because of recombination, the size of this ancestral haplotype is reduced considerably in course of time. However, recombinations may be more likely at specific locations, and the number of generations from the introduction of the disease mutation is not infinite.…”

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

“…12 Owing to the strong linkage disequilibria across the HLA complex, it is suspected that an allele of a linked locus, rather than DR3 itself, is responsible for these associations. 21,22 Regarding the titers of anti-AChR autoantibodies, work in progress from our laboratory points to an allele of a microsatellite marker in the central region of HLA, designated as TNFD*1, as explaining the variance of autoantibody titers better than DR3. The TNFD marker is located in the central region of HLA, in the third intron of the LST-1 gene, 650 kbp telomerically to HLA class II loci and 6 kbp centromerically to the TNF gene cluster ( Figure 2).…”

Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

“…In the absence of complete genotyping of all genes in the relevant regions and data from functional studies of candidate polymorphisms in these islands, haplotype mapping may help locate additional aetiological variants. 6,[14][15][16] This method relies on identifying recombination break points and blocks of LD and then measuring the disease association of the blocks, or ancestral haplotype segments.…”