Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset

Abstract

BackgroundJuvenile myasthenia gravis (MG) is a rare autoantibody mediated autoimmune disorder targeting the neuromuscular endplate. The clinical hallmark is muscle weakness and fatigability. Disease aetiology is complex, including both genetic and environmental factors. The involvement of genes in the human leukocyte antigen (HLA) is well established in adult MG. However, HLA associations in European juvenile MG have not been studied. This case-control study aimed to investigate and characterize genetic risk factors in prepubertal and postpubertal onset juvenile MG.Methodology/Principal findingsA population based Norwegian cohort of 43 juvenile MG patients (17 with prepubertal onset, 26 with postpubertal onset) and 368 controls were included. Next generation sequencing of five HLA loci (HLA-A, -B, -C, -DRB1 and -DQB1) was performed, and a positive association was seen with HLA-B*08 (OR (95% CI) = 3.27 (2.00–5.36), Pc = 0.00003) and HLA-DRB1*04:04 (OR (95% CI) = 2.65 (1.57–4.24), Pc = 0.03). Stratified in postpubertal and prepubertal onset, HLA-DRB1*04:04 was only positively associated with the latter (P = 0.01). The HLA-B*08 allele (12.9% in the controls), previously described associated with early onset adult MG, was most frequently observed in postpubertal onset MG (40.4%, P = 0.0002) but also increased among prepubertal onset MG (23.5%, P = 0.05).ConclusionThis study provides novel information about HLA susceptibility alleles in Norwegian juvenile MG where HLA-DRB1*04:04 was associated with prepubertal onset.

Autoimmune diseases and 8.1 ancestral haplotype: An update

“…In European populations, the HLA‐B*08 is associated with early onset MG (onset <40 years), whereas DRB1*15:01 allele has strongly been reported in late onset MG (onset >60 years) . A recent study also reported a positive association between the HLA‐DRB1*04:04 allele and juvenile MG onset (onset <12 years) …”

“…66 A recent study also reported a positive association between the HLA-DRB1*04:04 allele and juvenile MG onset (onset <12 years). 67 Additionally, a high-throughput sequencing of the entire MHC region and a GWAS study was performed in patients with early onset MG, in order to identify new possible markers inside and outside of the MHC region that may interact with the HLA-B*08:01 allele. Fascinatingly, it was found no other polymorphisms, suggesting that the HLA-B*08:01 is the unique genetic factor within the HLA region responsible for early-onset of MG in individuals with 8.1 AH.…”

The Epidemiology and Phenotypes of Ocular Manifestations in Childhood and Juvenile Myasthenia Gravis: A Review

“…Although many HLA association studies have been performed in adults with MG, those in juveniles and children are sparse, but may suggest that juvenile and/or ocular MG may have a distinct immunological basis in certain populations ( Table 3 ). For example, children from Norway showed an association with DRB1 * 04 ( 61 ) whereas those from Asia were associated with DRB1 * 09 . Childhood-onset ocular MG in Japanese and Chinese children, who were predominantly AChR-Ab negative, have shown reasonably consistent HLA-B * 4601; DRB1 * 0901 associations.…”

Childhood myasthenia gravis in Japan: Pathophysiology and treatment options

“…The difference in the epidemiological frequency of disease by race is thought to be due to immunogenetic differences, and several HLA differences have been reported. Popperud et al, in their study of Norwegians, reported that adolescent-onset MG is more frequently HLA-DRB1*0404, 19 20 In Japanese pediatric MG, Matsuki et al reported a high frequency of HLA-DR9 and DRw13, 21 Shinomiya et al reported a high frequency of HLA-DRB1*1302/DQA1*0102/DQB1*0604 or HLA-DRB1*0901/ DQA1*0301/DQB1*0303, 22 and Kida et al also reported a high frequency of HLA-DRw9 in ocular MG patients and HLA-DRw8 in generalized MG patients, including both children and adults. 23 These findings suggest that the high prevalence of ocular MG not only in Japanese but also in East Asia may be related to the fact that they share a common HLA type that differs from that in Western Europe.…”

“…The difference in the epidemiological frequency of disease by race is thought to be due to immunogenetic differences, and several HLA differences have been reported. Popperud et al, in their study of Norwegians, reported that adolescent‐onset MG is more frequently HLA‐DRB1*0404, 19 and Feng et al reported that HLA‐A*02:07:01‐B*46:01:01‐C*01:02:01‐DQA1*01:01:01‐DQB1*03:03:02‐DRB1*09:01:02 haplotype is common in Chinese infant MG 20 . In Japanese pediatric MG, Matsuki et al reported a high frequency of HLA‐DR9 and DRw13, 21 Shinomiya et al reported a high frequency of HLA‐DRB1*1302/DQA1*0102/DQB1*0604 or HLA‐DRB1*0901/DQA1*0301/DQB1*0303, 22 and Kida et al also reported a high frequency of HLA‐DRw9 in ocular MG patients and HLA‐DRw8 in generalized MG patients, including both children and adults 23 .…”