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

The distribution limit of the common tick, Ixodes ricinus, and some associated pathogens in north-western Europe

In north-western Europe, the common tick, Ixodes ricinus, is widely established, its distribution appears to be increasing and the spread of tick-borne diseases is of increasing concern. The project ‘Flått i Nord’ (Ticks in northern Norway) commenced in spring 2009 with the intention of studying the tick’s distribution and that of its pathogens in northern Norway. Several methods were used: cloth-dragging, collecting from trapped small mammals, and collecting from pets. Since 2010, the occurrence of ticks in the region of northern Norway was determined directly by cloth-dragging 167 times in 109 separate locations between the latitudes of 64 °N and 70 °N (included seven locations in the northern part of Trøndelag County). The northernmost location of a permanent I. ricinus population was found to be Nordøyvågen (66.2204 °N, 12.59 °E) on the Island of Dønna. In a sample of 518 nymphal and adult ticks, the Borrelia prevalence collected close to this distribution limit varied but was low (1–15 %) compared with the locations in Trøndelag, south of the study area (15–27 %). Five specimens (1 %) were positive for Rickettsia helvetica. The length of the vegetation growing season (GSL) can be used as an approximate index for the presence of established populations of I. ricinus. The present study suggests that the threshold GSL for tick establishment is about 170 days, because the median GSL from 1991 to 2015 was 174–184 days at sites with permanent tick populations, showing a clear increase compared with the period 1961–1990. This apparent manifestation of climate change could explain the northward extension of the range of I. ricinus.publishedVersio

The distribution limit of the common tick, Ixodes ricinus, and some associated pathogens in north-western Europe

In north-western Europe, the common tick, Ixodes ricinus, is widely established, its distribution appears to be increasing and the spread of tick-borne diseases is of increasing concern. The project ‘Flått i Nord’ (Ticks in northern Norway) commenced in spring 2009 with the intention of studying the tick’s distribution and that of its pathogens in northern Norway. Several methods were used: cloth-dragging, collecting from trapped small mammals, and collecting from pets. Since 2010, the occurrence of ticks in the region of northern Norway was determined directly by cloth-dragging 167 times in 109 separate locations between the latitudes of 64 °N and 70 °N (included seven locations in the northern part of Trøndelag County). The northernmost location of a permanent I. ricinus population was found to be Nordøyvågen (66.2204 °N, 12.59 °E) on the Island of Dønna. In a sample of 518 nymphal and adult ticks, the Borrelia prevalence collected close to this distribution limit varied but was low (1–15 %) compared with the locations in Trøndelag, south of the study area (15–27 %). Five specimens (1 %) were positive for Rickettsia helvetica. The length of the vegetation growing season (GSL) can be used as an approximate index for the presence of established populations of I. ricinus. The present study suggests that the threshold GSL for tick establishment is about 170 days, because the median GSL from 1991 to 2015 was 174–184 days at sites with permanent tick populations, showing a clear increase compared with the period 1961–1990. This apparent manifestation of climate change could explain the northward extension of the range of I. ricinus

The distribution limit of the common tick, Ixodes ricinus, and some associated pathogens in north-western Europe

In north-western Europe, the common tick, Ixodes ricinus, is widely established, its distribution appears to be increasing and the spread of tick-borne diseases is of increasing concern. The project Flatt i Nord (Ticks in northern Norway) commenced in spring 2009 with the intention of studying the ticks distribution and that of its pathogens in northern Norway. Several methods were used: cloth-dragging, collecting from trapped small mammals, and collecting from pets. Since 2010, the occurrence of ticks in the region of northern Norway was determined directly by cloth-dragging 167 times in 109 separate locations between the latitudes of 64 degrees N and 70 degrees N (included seven locations in the northern part of Trondelag County). The northernmost location of a permanent I. ricinus population was found to be Nordoyvagen (66.2204 degrees N, 12.59 degrees E) on the Island of Donna. In a sample of 518 nymphal and adult ticks, the Borrelia prevalence collected close to this distribution limit varied but was low (1-15 %) compared with the locations in Trondelag, south of the study area (15-27 %). Five specimens (1 %) were positive for Rickettsia helvetica. The length of the vegetation growing season (GSL) can be used as an approximate index for the presence of established populations of I. ricinus. The present study suggests that the threshold GSL for tick establishment is about 170 days, because the median GSL from 1991 to 2015 was 174-184 days at sites with permanent tick populations, showing a clear increase compared with the period 1961-1990. This apparent manifestation of climate change could explain the northward extension of the range of I. ricinus.Funding Agencies|Medical Research Council of Southeast Sweden (FORSS) [657881]; Division of Laboratory Medicine, Region Jonkoping County, Sweden; EFSA; European Food Safety Authority; ECDC, the European Centre for Disease Prevention and Control; Northern Norway Regional Health Authority (Helse Nord RHF), Norway [SFP912-10]</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

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

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

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

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

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

Associated alleles in late onset myasthenia gravis (LOMG).

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