Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations

Abstract

Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13–HLA-DR–HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG.

Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study

“…As with previous GWASes of myasthenia gravis ( 7 , 8 ), our study identified the HLA locus as a susceptibility locus for this autoimmune disease. Despite the individual-level and population-level variability intrinsic to this locus, our results agreed with a recent study of HLA Class I and II effects on early-onset and late-onset myasthenia gravis risk in the Norwegian, Swedish, and Italian populations ( 23 ). This served as an additional replication cohort and underscored the veracity of our results.…”

Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes

“…On the other hand, Lambert-Eaton myasthenic syndrome (LEMS) associates with voltage-gated calcium channels (VGCC) autoantibodies, and small-cell lung cancer (SCLC) is present in approximately 50% of the patients [16]. Strikingly, both nonparaneoplastic EOMG and LEMS are associated with the ancestral HLA haplotype 8.1 (AÃ01 : 01$BÃ08 : 01$DQA1Ã05 : 01$DQB1Ã02 : 01-$DRB1Ã03 : 01) in white populations, while paraneoplastic subjects lack this association [18][19][20][21][22][23][24]. This haplotype is largely known to be related to several autoimmune diseases, including type 1 diabetes mellitus (T1DM) and celiac disease [25].…”