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From INSERM U25 (Drs. Beaurain and Garchon, and M. Giraud), Centre de l’Association Claude Bernard (Dr. Beaurain), and Laboratoire Central d’Immunologie (Dr. Yamamoto), Hôpital Necker, Paris; Service de Neurologie (Dr. Eymard), Institut de Myologie, Hôpital de la Salpêtrière, Paris; Service de Neurologie (Dr. Tranchant), Hôpital Civil, CHRU Strasbourg; and Service de Réanimation (Dr. Gajdos), Hôpital Raymond Poincaré, Garches, France.
Address correspondence and reprint requests to Dr. H.-J. Garchon, INSERM U25, Hôpital Necker, 161 rue de Sèvres, 75743 Paris cedex 15, France; e-mail: garchon{at}necker.fr
Background:— MG is an autoimmune disease of the neuromuscular junction. MG with thymus hyperplasia has been associated with, but not genetically linked to, the HLA-DR3 haplotype.
Objective:— To re-evaluate the association of HLA with MG in 656 patients with generalized disease and to test linkage of HLA to MG with thymus hyperplasia.
Method:— Patients were genotyped for HLA-DRB1. Data analysis included case-control comparisons after subgrouping patients by thymus histopathology. The transmission of parental alleles to MG offspring with thymus hyperplasia was studied in simplex families using the transmission/disequilibrium test (TDT) as a test of linkage.
Results:— MG with thymus hyperplasia was positively associated with DR3 (OR = 4.5, p = 1 x 10-6) and negatively associated with DR7 (OR = 0.28, p = 1 x 10-6), based on both case-control comparisons and TDT. No association was detected with thymomas. Conversely, patients who lacked thymus anomalies but expressed anti-titin antibodies (ATA) had an increase of DR7 (OR = 2.08, p = 4 x 10-3) and a decrease of DR3 (OR = 0.33, p = 9 x 10-3).
Conclusions:— The authors established linkage of HLA to MG and thymus hyperplasia, defining the MYAS1 locus. Moreover, DR3 and DR7, or closely linked genes, have opposing effects on MG phenotypes. Nonthymomatous patients with ATA may be a pathogenetically distinct subset of MG patients.
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