Factores genéticos que influyen en las formas familiares y esporádicas de miastenia gravis autoinmune

Abstract

Background: Autoinmune myasthenia gravis (MG) is a highly heterogenic disease in the clinical, serological and histological sense. Its etiology is considered multifactorial, involving genetic, environmental and epigenetic factors. The Human Leukocitary Antigens (HLA) is the most relevant genetic risk factor known to be associated to MG. The influence of major genes in the phenotypic expression of MG has been scarcely studied in the Spanish population. Hypothesis/aim: To study the influence of some genetic factors such as the multigenic HLA complex and/or some major genes like ENOX1, in the onset of the disease. Investigate their role as risk, susceptibility, protection or modificating factors of the clinical, serological and histological phenotype in sporadic forms of MG (SAMG), and to determine the frequency of mutations in these genes in a Spanish population. Patients and methods: 250 MG patients (including 16 family forms) from the Neuromuscular Disease unit of the HUVH were classified into subgroups according to age of onset of the disease and phenotypic characterization. Variables of study: age, age at the onset of the disease, sex, ethnicity and geographic origin, MGFA class, QMG (including the highest score of severity of the disease), pharmacological treatment received, thymectomy, post-interventional status, thymic histopathology antibody titers, autoimmune diseases affecting the patient and/or first-degree relatives. High-resolution NGS and genotype sequencing of HLA A/B/C/DRB1/DQB1 alleles and haplotypes and case-control statistical correlation were carried out. Sanger sequencing and KASPar genotyping of ENOX1 to identify potential risk/susceptibility variants related to MG. A control population of 2000 healthy bone marrow donors from the Blood and Tissue Bank of Barcelona were used for the HLA genotyping study; and 598 control samples and data from individuals without MG or other autoimmune disorders from the National DNA Bank (Salamanca's University) were used in the ENOX1 association study. Results/Conclusions: The prevalence of familial forms of MG (FAMG) in our cohort was similar to that of the main published studies (3. 46%) in other populations, with a late or very late onset predominance and with an enormous inter-/intrafamilial heterogeneity. The HLA complex plays a significant role as a risk, susceptibility and modifying factor of the SAMG phenotype, as reported in other European Caucasian populations (AH 8. 1). In our cohort we have identified new HLA associations: (1) DQB1*03:01 as a possible risk factor in women with early onset (EOMG), thymic hyperplasia and anti-AChR; (2) the possible protective effect against MG of A*24:02 in women; or (3) the DRB1*07:01 and DQB1*02:02 alleles as possible phenotype modifying factors for the very late onset forms of MG. In our families with FAMG, DRB1*03:01 and DQB1*02:01 were the most frequent alleles, although we could not associate them statistically to the phenotype. Additionally, we cannot rule out the influence of DQB1*05:03 and DRB1*14:54 as possible risk factors for FAMG in our population. With regard to the ENOX1 gene studies, we were unable to identify any pathogenic mutations in the FAMG or SAMG forms, but we found new single or haplotypical variants, which could act as risk factors for thymoma in MG (CGAC haplotype) or as modifying phenotype factors in the age of onset (rs1044753, haplotype CGGC). The etiopathogenic mechanisms of autoimmune MG are strikingly complex and most likely require the involvement of other currently unknown major genes, apart from the HLA complex or the ENOX1 gene. In order to identify these new genes, and to validate our results, multicentric genetic studies should be carried out with larger sample sizes.

Date of Award	7 Feb 2020
Original language	Spanish
Supervisor	José Gamez Carbonell (Director), José Manuel Vidal Taboada (Director) & Jose Alvarez Sabin (Tutor)