Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia

Abstract

The 8.1 haplotype of the HLA complex has been reproducibly associated with several autoimmune diseases and traits, notably with thymus hyperplasia in patients with acquired generalized myasthenia gravis, an autoantibody-mediated disease directed at the muscle acetylcholine receptor. However, the strong linkage disequilibrium across this haplotype has prevented the identification of the causative locus, termed MYAS1. Here, we localized MYAS1 to a 1.2-Mb genome segment by reconstructing haplotypes and assessing their transmission in 73 simplex families. This segment encompasses the class III and proximal class I regions, between the BAT3 and C3-2-11 markers, therefore unambiguously excluding the class II loci. In addition, a case-control study revealed a very strong association with a core haplotype in this same region following an additive model (P ‫؍‬ 7 ؋ 10 ؊11 , odds ratio 6.5 for one copy and 42 for two copies of the core haplotype). Finally, we showed that this region is associated with a marked increase in serum titers of anti-acetylcholine receptor autoantibodies (P ‫؍‬ 8 ؋ 10 ؊6 ). Remarkably, this effect was suppressed by a second locus in cis on the 8.1 haplotype and located toward the class II region. Altogether, these data demonstrate the highly significant but complex effects of the 8.1 haplotype on the phenotype of myasthenia gravis patients and might shed light on its role in other autoimmune diseases.

Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases

“…Prior studies had suggested that the class I region has a role in susceptibility (42,43). The current analysis reveals that, compared with the other autoimmune disorders, the genetic role of the MHC in MG is distinctive, consisting of a single signal in the class I region, specifically in the vicinity of the HLA complex protein 5 gene (HCP5) located between MICA and MICB.…”

Several Regions in the Major Histocompatibility Complex Confer Risk for Anti-CCP-Antibody Positive Rheumatoid Arthritis, Independent of the DRB1 Locus

“…A wide array of autoimmune phenotypes has been associated with this haplotype, including systemic lupus erythematosus (29), autoimmune hepatitis, and myasthenia gravis (25). Interestingly, recent data suggest that DRB1 is not the primary locus of risk for Myasthenia Gravis (30). Truncated 8.1 haplotypes that lack the DR3 allele are associated with higher levels of acetylcholine receptor autoantibodies in subjects with Myasthenia Gravis, and the primary association with disease appears to lie telomeric to the Class II region.…”

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

“…In addition to chromosome 6 painting, the AF129756 BAC (The Sanger Institute) encompassing most of the class III region was used as a second probe to verify MHC integrity. Genotypes of HLA classical molecules (HLA-A, B, C, DR, and DQ) were verified by the Tissue Typing Laboratory in Oxford (Dr. Barnardo Martin), while the homozygosity and genotypes of microsatellites along the class III region (D6S272, D6S2800, MICA, TNFb, and D6S2789) were checked as described before (Vandiedonck et al 2004). Apart from D6S272, which showed heterozygosity for PGF, all other markers showed the expected genotypes.…”