Immunoglobulin heavy chain gene associations in myasthenia gravis: new evidence for disease heterogeneity.

Susceptibility to myasthenia gravis (MG) is known to involve genes residing in the major histocompatibility complex class I and II regions (HLA-B8 and DR3). Immunoglobulin heavy chain constant region (IgCH) allotypes have also shown some associations with MG. We have used restriction fragment length polymorphism analysis with probes to the IgCH switch (S) regions mu and alpha 1 and the downstream marker D14S1 to investigate 189 Caucasoid patients with well-defined MG. A highly significant increase in the frequency of the 2.6 kilobase (kb) S mu homozygous genotype and the 2.6 kb S mu allele was found in patients with disease onset after the age of 40 years (late onset) compared with normal controls (P less than 0.00075 and P less than 0.025 respectively). No association was found at the S alpha 1 or D14S1 loci. In patients with an associated thymoma there was a moderate increase in the frequency of the 2.6 kb S mu and 7.4 kb S alpha 1 genotypes. These results independently support the previous separation of the late-onset subgroup. Finally, the stronger association at S mu rather than at the downstream S alpha 1, Gm and D14S1 loci suggest that the genes predisposing to MG are located within the variable region of the Ig heavy chain loci.