Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population

Angelina H Maniaol,Åslaug R Lorentzen,Ahmed Elsais,Hanne F Harbo,Rune Midgard,Geir Bråthen,Nils Erik Gilhus,Margitta T Kampman,Benedicte A Lie,Chantal M E Tallaksen,Hanne Sæther,Siri T Flåm,Jone F Owe,Marte Christensen,Anna Rognerud,Marte K Viken,Emilia Kerty

doi:10.1371/journal.pone.0036603

Abstract

BackgroundAcquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG.Methodology/Principal FindingsThis case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥60years) (OR 2.38, pc7.4×10−5). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, pc 4.71×10−4), a finding not previously described. No significant association was found to the DRB1*07:01 allele (pnc = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies.ConclusionThe results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.

Highlights

Acquired myasthenia gravis (MG) is a rare autoimmune neuromuscular disease with an overall prevalence of 10–20 per 100 000 [1]
The results from this study provide important new information concerning the susceptibility of human leukocyte antigen (HLA) alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in late onset MG (LOMG)
This study aimed to investigate a large Norwegian MG population with well defined subgroups of patients, and carry out comprehensive genotyping of HLA Class I and II loci in order to better characterise the genetic risk factors in MG subgroups In particular, we aimed to focus on finding the major HLA risk allele in the LOMG subgroup

Summary

Introduction

Acquired myasthenia gravis (MG) is a rare autoimmune neuromuscular disease with an overall prevalence of 10–20 per 100 000 [1]. MG is caused by impaired neuromuscular transmission leading to abnormal muscle fatigability affecting in some cases only the eye muscles (ocular MG), but in most cases several muscles groups (generalised MG) [2,3]. The muscle fatigability is mediated by pathogenic autoantibodies against the muscle acetylcholine receptors (AChR-abs) detectable in the majority of patients (80–85%) [4]. MG is characterized by remarkable heterogeneity, including degree of thymus involvement and clinical presentation like age at onset, disease severity and response to treatment [8]. Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG

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