Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients

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Abstract

Background and objective

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. MG has been shown to be associated with many human leukocyte antigens (HLA) in different populations. The aim of this study was to investigate the probable association between HLA-DR/DQ alleles and MG in Tunisian patients.

Patients and methods

HLA DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) with 48 MG patients and 100 healthy individuals serving as the control group.

Results

Myasthenia gravis in Tunisian patients was found to be associated with the following alleles (pc denotes Bonferroni corrected probability values): HLA-DRB1*03 (pc < 10−3), DRB1*04 (pc = 0.005), DQB1*02 (pc = 0.002) and, DQB1*03 (pc = 0.007).

Conclusion

Our data demonstrated a new HLA-MG predisposition with DRB1*04. The DRB1*03, DRB1*04, DQB1*02, and DQB1*03 alleles also could be predisposing genetic factors for MG in the Tunisian population.

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.

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