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.
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 MGpatients.
Authors: Peter K Gregersen; Roman Kosoy; Annette T Lee; Janine Lamb; Jon Sussman; David McKee; Kim R Simpfendorfer; Ritva Pirskanen-Matell; Frederik Piehl; Qiang Pan-Hammarstrom; Jan J G M Verschuuren; Maarten J Titulaer; Erik H Niks; Alexander Marx; Philipp Ströbel; Björn Tackenberg; Michael Pütz; Angelina Maniaol; Ahmed Elsais; Chantal Tallaksen; Hanne F Harbo; Benedicte A Lie; Soumya Raychaudhuri; Paul I W de Bakker; Arthur Melms; Henri-Jean Garchon; Nicholas Willcox; Lennart Hammarstrom; Michael F Seldin Journal: Ann Neurol Date: 2012-10-10 Impact factor: 10.422
Authors: Ning Wang; Nan Shen; Timothy J Vyse; Vidya Anand; Iva Gunnarson; Gunnar Sturfelt; Solbritt Rantapää-Dahlqvist; Kerstin Elvin; Lennart Truedsson; Bengt A Andersson; Charlotte Dahle; Eva Ortqvist; Peter K Gregersen; Timothy W Behrens; Lennart Hammarström Journal: Mol Med Date: 2011-08-04 Impact factor: 6.354
Authors: John D Rioux; Philippe Goyette; Timothy J Vyse; Lennart Hammarström; Michelle M A Fernando; Todd Green; Philip L De Jager; Sylvain Foisy; Joanne Wang; Paul I W de Bakker; Stephen Leslie; Gilean McVean; Leonid Padyukov; Lars Alfredsson; Vito Annese; David A Hafler; Qiang Pan-Hammarström; Ritva Matell; Stephen J Sawcer; Alastair D Compston; Bruce A C Cree; Daniel B Mirel; Mark J Daly; Tim W Behrens; Lars Klareskog; Peter K Gregersen; Jorge R Oksenberg; Stephen L Hauser Journal: Proc Natl Acad Sci U S A Date: 2009-10-21 Impact factor: 11.205
Authors: Michael F Seldin; Omar K Alkhairy; Annette T Lee; Janine A Lamb; Jon Sussman; Ritva Pirskanen-Matell; Fredrik Piehl; Jan J G M Verschuuren; Anna Kostera-Pruszczyk; Piotr Szczudlik; David McKee; Angelina H Maniaol; Hanne F Harbo; Benedicte A Lie; Arthur Melms; Henri-Jean Garchon; Nicholas Willcox; Peter K Gregersen; Lennart Hammarstrom Journal: Mol Med Date: 2015-11-10 Impact factor: 6.354
Authors: J S Yi; A Guidon; S Sparks; R Osborne; V C Juel; J M Massey; D B Sanders; K J Weinhold; J T Guptill Journal: J Autoimmun Date: 2013-12-28 Impact factor: 7.094