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

BACKGROUND: Acquired 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 FINDINGS: This 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 ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 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. CONCLUSION: The 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

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

Background: Acquired 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 Findings: This 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. Conclusion: The 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

Myasthenia Gravis: A Review of Available Treatment Approaches

Patients with autoimmune myasthenia gravis (MG) should be further classified before initiating therapy, as treatment response varies for ocular versus generalised, early onset versus late onset, and acetylcholine receptor antibody positive versus MuSK antibody positive disease. Most patients need immunosuppression in addition to symptomatic therapy. Prednisolone and azathioprine represent first choice drugs, whereas several second choice options are recommended and should be considered. Thymectomy should be undertaken in MG with thymoma and in generalised, early-onset MG. For MG crises and other acute exacerbations, intravenous immunoglobulin (IvIg) and plasma exchange are equally effective and safe treatments. Children and females in child bearing age need special attention regarding potential side effects of immunosuppressive therapy. MG pathogenesis is known in detail, but the immune therapy is still surprisingly unspecific, without a pin-pointed attack on the defined disease-inducing antigen-antibody reaction being available

Clinical characteristics of the Norwegian myasthenia gravis study cohort (n = 369).

1<p>According to MGFA classification <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036603#pone.0036603-JaretzkiA1" target="_blank">[39]</a>: ocular MG (MGFA grade I), generalised MG (MGFA grade II-V), not available in 12 cases.</p>2<p>Concomitant immune-mediated diseases include thyroid disease (hypo-, hyperthyroidsm, thyroiditis), type 1-diabetes, rheumatic diseases, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel diseases (Crohńs disease or ulcerative colitits). EOMG = early onset MG; LOMG = late onset MG; AChR-ab+  =  acetylcholine receptor-antibody positive.</p

The association between HLA loci and myasthenia gravis subgroups (p-values).

<p>EOMG = early onset MG, LOMG = late onset MG.</p><p>P-values are not corrected, p<0.01 is considered significant after correction for multiple comparisons (n = 4).</p

Conditional analyses of the HLA-A, -B, -C and DRB1 loci (p-values) in early onset myasthenia gravis (EOMG).

<p>P-values are not corrected, p<0.01 is considered significant after correction for multiple comparisons (n = 4).</p

Assessment of the strongest association on the HLA-B*08-DRB1*03:01 haplotype in early onset myasthenia gravis (EOMG).

<p>+  =  positives, −  =  negatives.</p

Schematic overview of associated HLA alleles in MG.

<p>The HLA complex on chromosome 6 with its division into three classes. Some key genes and their order on the chromosome are given. Associated HLA alleles reported earlier in Caucasian MG patients (see text for complete references) are illustrated together with the results from the present study.</p

The most strongly associated HLA alleles in early onset myasthenia gravis (EOMG).

<p>Odds Ratio (OR) and 95% confidence interval (CI) are shown for nominal p-values.</p