Maria Salvado1,2,3, Jose Luis Caro4, Cecilia Garcia2, Francesc Rudilla5,6, Laura Zalba-Jadraque2, Eva Lopez2, Elia Sanjuan2, Josep Gamez7, Jose Manuel Vidal-Taboada8. 1. Myasthenia Gravis Unit. Clinic of Neuromuscular Disorders and Rare Diseases, Neurology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 2. Peripheral Nervous System, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain. 3. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. 4. Immunology Department, Biomedic Diagnostic Center, Hospital Clínic de Barcelona, Barcelona, Spain. 5. Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain. 6. Transfusional Medicine, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain. 7. Neurology Department, GMA Clinics, Universitat Autònoma de Barcelona, Barcelona, Spain. josepgamez.bcn@gmail.com. 8. Peripheral Nervous System, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain. jose.vidal@vhir.org.
Abstract
BACKGROUND: Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort. METHODS: We designed a clinical case-control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)-based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status. RESULTS: We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype.
BACKGROUND: Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort. METHODS: We designed a clinical case-control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)-based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status. RESULTS: We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype.
Authors: Loukas Moutsianas; Luke Jostins; Ashley H Beecham; Alexander T Dilthey; Dionysia K Xifara; Maria Ban; Tejas S Shah; Nikolaos A Patsopoulos; Lars Alfredsson; Carl A Anderson; Katherine E Attfield; Sergio E Baranzini; Jeffrey Barrett; Thomas M C Binder; David Booth; Dorothea Buck; Elisabeth G Celius; Chris Cotsapas; Sandra D'Alfonso; Calliope A Dendrou; Peter Donnelly; Bénédicte Dubois; Bertrand Fontaine; Lars Fugger; An Goris; Pierre-Antoine Gourraud; Christiane Graetz; Bernhard Hemmer; Jan Hillert; Ingrid Kockum; Stephen Leslie; Christina M Lill; Filippo Martinelli-Boneschi; Jorge R Oksenberg; Tomas Olsson; Annette Oturai; Janna Saarela; Helle Bach Søndergaard; Anne Spurkland; Bruce Taylor; Juliane Winkelmann; Frauke Zipp; Jonathan L Haines; Margaret A Pericak-Vance; Chris C A Spencer; Graeme Stewart; David A Hafler; Adrian J Ivinson; Hanne F Harbo; Stephen L Hauser; Philip L De Jager; Alastair Compston; Jacob L McCauley; Stephen Sawcer; Gil McVean Journal: Nat Genet Date: 2015-09-07 Impact factor: 38.330