Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies.
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.


METHODS
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.
Giraud
M
M
INSERM U25, Hôpital Necker, Paris, France.
Beaurain
G
G
Yamamoto
A M
AM
Eymard
B
B
Tranchant
C
C
Gajdos
P
P
Garchon
H J
HJ
D000328:Adult; D001323:Autoantibodies / Q000032:analysis; D016022:Case-Control Studies; D064211:Connectin; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D015803:HLA-DR3 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009124:Muscle Proteins / Q000276:immunology*; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D011494:Protein Kinases / Q000276:immunology*; D013950:Thymus Gland / Q000473:pathology; D013952:Thymus Hyperplasia / Q000235:genetics / Q000276:immunology / Q000473:pathology
D001323:Autoantibodies; D064211:Connectin; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D059811:HLA-DRB1 Chains; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases