Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients
Introduction
Myasthenia gravis (MG) is a rare and heterogeneous autoimmune disease characterized by progressive weakness and fatigue of the voluntary musculature. It is caused by immune-mediated loss of functioning acetylcholine receptors (AChR) from the post-synaptic membrane of the neuromuscular junction [1], [2].
The association with human leukocyte antigens (HLA) has been known since the early 1970s [3], [4]. These antigens strongly influence susceptibility to the development of MG [5], [6].
In Caucasian populations, the most commonly cited alleles in the HLA complex that have been associated with MG are DRB1*03, DQB1*02, and DQB1*03 [7], [8].
Studies of different populations have revealed that the frequencies of different HLA antigens vary depending on sex, age at disease onset, ethnic, and geographic origins of these populations [9].
In this study, we have genotyped HLA class II alleles in Tunisian MG patients and examined HLA class II association with MG subjects to understand HLA genotype effects on disease pathogenesis.
Section snippets
Subjects
Forty-eight (22 women and 26 men) unrelated Tunisian MG patients were studied (male to female ratio = 1.18). The patients were referred from all regions of the country and were selected to have the generalized type of myasthenia; all other types were excluded. Myasthenia gravis was diagnosed according to conventional clinical criteria, electromyography, and/or a positive acetylcholine receptor antibodies test. The neostigmine test was positive for all patients. In AChR seronegative patients, the
Clinical and immunological characteristics
Table 1 summarizes the main clinical characteristics of the 48 unrelated Tunisian patients. The age at onset of disease ranged from 11 years to 76 years (mean 38.75 years). A cutoff age of 40 years was used to distinguish early onset (30 patients) from late onset (18 patients) of the disease. A serum anti-AChR antibody titer under 0.2 nmol/L was defined as negative.
HLA-DRB/DQB allele
Table 2 (section a) shows the frequencies of DRB1, 3, 4 and 5 alleles in patients and controls. The prevalence of DRB1*03 and
Discussion
MG is a heterogeneous disease that appears to occur in genetically susceptible individuals. Previously reported data associated this disease with various HLAs. In the present study, DRB and DQB allele distributions were investigated in Tunisian MG patients and compared with healthy controls.
The genetics underlying the autoimmune response in MG is not well understood; although different HLA antigens have been frequently associated with disease in diverse ethnic populations [10], [11].
Our study
Acknowledgments
We would like to thank Dr. Christian Winchell for his precious help in correcting this manuscript, and G. Bouaicha for her technical support.
References (30)
- et al.
MHC genes in autoimmunity
Current Opinion in Immunology
(1993) - et al.
Identification by genomic typing of non-DR3 HLA class II genes associated with myasthenia gravis
Journal of Neuroimmunology
(1993) - et al.
HLA class II and class I polymorphism in Venezuelan patients with myasthenia gravis
Human Immunology
(2004) - et al.
HLA-DQ polymorphism in Turkish patients with myasthenia gravis
Human Immunology
(2006) - et al.
Polymorphic amino acid domains of the HLA-DQ molecule are associated with disease heterogeneity in myasthenia gravis
Journal of Neuroimmunology
(1996) - et al.
A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan
Clinical Immunology
(2004) - et al.
Myasthenia gravis and HLA antigens in American blacks and other races
Journal of Neuroimmunology
(1984) - et al.
HLA alleles and haplotypes in French North African immigrants
Human Immunology
(2006) - et al.
HLA-A, -B, -DR and -DQ allele and haplotype frequencies in the Moroccan population: a general population study
Transfusion Clinique et Biologique
(2006) - et al.
HLA-DRB1 and DQB1 polymorphisms in Southern France and genetic relationships with other Mediterranean populations
Human Immunology
(2000)
Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics
Human Immunology
Correlation of thymic pathology with HLA in myasthenia gravis
Clinical Immunology
HLA polymorphism in type 1 diabetes Tunisians
Annales de Genetique
Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients
Annals of Surgery
Cited by (24)
Immunogenetics and its utility in therapeutics
2022, Immunogenetics: a Molecular and Clinical Overview: Clinical Applications of Immunogenetics, Volume IIHuman leukocyte antigens (HLA) association with myasthenia gravis (MG) and its myasthenia manifestations in Algerian patients
2021, Meta GeneCitation Excerpt :Given the relatively high frequency of the allele A*30 in North African populations (Arnaiz-Villena et al., 1995; Brick et al., 2015; Hmida et al., 1995) compared to other populations and because this is the first study to investigate MG and class I HLA associations in Algerian/North African populations, we might assume that the allele A*30 predisposing effect is characteristic of these populations. The similar study conducted on a Tunisian population reported that the allele DRB1*04 was associated with the susceptibility to MG (Fekih-Mrissa et al., 2013), Our results are in the same line with this . However, the study also reported a strong association of the allele DRB1*03, which was also reported to be associated with MG in several other populations by different groups (M Giraud et al., 2001; Santos et al., 2017; Zhong et al., 2019).
HLA and age of onset in myasthenia gravis
2017, Neuromuscular DisordersCitation Excerpt :Recent studies described different HLA allele associations to LOMG. A Tunisian study described an association with HLA-DRB1*04 allele [28], a Norwegian study with HLA-DRB1*15 [12] and an Italian study with HLA-DQB1*05:02 and DRB1*16 alleles to LOMG [13]. Our findings regarding the EOMG and LOMG were still value even when dividing the patients in subgroups just considering the age and not thymic pathology.
Elderly-onset familial myasthenia gravis in two siblings
2016, Neuromuscular DisordersCitation Excerpt :Familial occurrence of MG may be related to certain HLA alleles. Several studies have shown the association of specific HLA alleles with MG in different populations [4–8]. HLA-DR15 was significantly increased in patients with late-onset MG (≥50 years) compared with patients with early-onset MG (<40 years) in a Japanese cohort [4], and an allele of HLA-DR15, HLA-DRB1*15:01, was associated with patients with late-onset MG (≥60 years) in a Norwegian cohort [8].
Association of HLA-DR/DQ polymorphism with alzheimer's disease
2015, American Journal of the Medical SciencesCitation Excerpt :In addition, some studies failed to find any significant associations between disease and either HLA-DR or -DQ alleles.6,30 Several examples of associations between immune-mediated diseases with specific HLA alleles have been reported.15–17 These associations vary in strength and in the alleles implicated.
Association of HLA-DR/DQ polymorphisms with Guillain-Barré syndrome in Tunisian patients
2014, Clinical Neurology and NeurosurgeryCitation Excerpt :The human leukocyte antigen (HLA) complex is crucial for immunity and its polymorphisms are specifically associated with autoimmune inflammatory diseases [7]. Several genetic studies show that the major histocompatibility complex (MHC) genes, especially HLA antigens represent the strongest risk for developing several diseases with autoimmune features [8,9]. Because GBS was thought to have an immune-mediated, possibly autoimmune component, the HLA molecules carried by patients with this disorder have been evaluated in several studies.