Study Suggests Genetic Link Between HLA Alleles, MG

New research has identified a significant correlation between 2 human leucocyte antigen (HLA) alleles and the prevalence of myasthenia gravis (MG), according to a report recently published in Cureus.¹

The study examined the relationship between the prevalence of MG in various geographic regions worldwide and the frequency of certain HLA alleles in those same locations. By identifying specific alleles associated with MG, the authors wrote, it may be possible to screen people at risk of developing MG.

Once the HLA antigens associated with MG were established, the investigators assessed the prevalence of MG in various geographic regions around the world. | Image Credit: © ktsdesign - stock.adobe.com

“Although much has been done to provide a brighter prognosis, research into the correlation between HLA alleles and MG may provide a better understanding of the disease and potentiate a screening tool for early detection and management,” the authors wrote.

Alleles are a pair of matched genes, one inherited from each biological parent. HLA alleles are classified as Class I, II, and III based on function and distribution, with Class II alleles more strongly associated with autoimmune diseases. Some HLA alleles are more common in certain populations, which makes it possible to study the correlation between specific alleles and the development of MG.

MG is an autoimmune disease characterized by fatigue and profound muscle weakness in certain groups of muscles, although early symptoms can be subtle and varied. As muscle weakness is a clinical finding in many conditions, it can be difficult to diagnose MG.   

While current treatments for MG can improve symptoms, there is no cure, the authors wrote. Furthermore, population-based studies from the last 50 years have clearly shown an increase in prevalence attributed to aging populations in developed countries. Interestingly, women aged 20 to 30 years demonstrate a 2:1 prevalence of the disease relative to men, whereas the disease more commonly affects men after the age of 50. As the world’s population is aging, the incidence of MG in men is now higher than in women.

The investigators searched Scopus and PubMed and other sources to find appropriate studies dating from 1990 to 2017. In total, 6 studies identified 8 HLA Class II alleles associated with MG. However, frequency data from allelefrequencies.net showed only 2 alleles—DRB1*04.04 (P = 0.032) and DRB1*03 (P = 0.030)—with a statistically significant association between the frequency of HLA alleles and MG prevalence. Both alleles also demonstrated a correlation coefficient (r) of 0.75, which, the authors suggested, could predispose individuals to the development of MG.

However, other HLA Class 2 alleles, including DRB1*01, DQB1*02, and DRB1*04, showed a positive yet weaker correlation with the prevalence of MG, with r values of 0.51, 0.64, and 0.48, respectively. In these cases, statistical analysis calculated a P value greater than .05, indicating a statistically insignificant correlation.

Once the HLA antigens associated with MG were established, the investigators assessed the prevalence of MG in various geographic regions around the world. The 10 countries captured in this analysis were then grouped into 4 broad regions: Asia, Northern Europe, Eastern Europe, and the Americas.

Study results highlighted that:

• Northern European countries (Norway, Sweden, and Denmark) and an Eastern European country (Serbia) had the highest prevalence of MG.
• Asian countries (Korea, Taiwan, and Japan) showed a much lower prevalence.
• Countries in the Americas displayed the greatest variety in prevalence (Mexico, 11.1 cases vs Columbia, 1.78 cases).

The investigators stressed they did not include data beyond 2017 due to possible effects of COVID-19 on the prevalence of MG. In fact, a review of studies from January 2000 to October 2021 did reveal an increased risk of developing new-onset MG for patients infected with COVID-19.²

“The mechanism of action is thought to be due to a SARS-CoV-2 infection causing a release of inflammatory cytokines and a cytokine storm,” the authors wrote.¹ “This results in immune dysregulation and an increased risk of developing MG in susceptible patients,” they explained.

Overall, the current study supports the idea that certain alleles that may predispose people to the development of MG. Northern European countries were found to have both the highest prevalence of MG and the highest prevalence of alleles DRB1*04.04 and DRB1*03.

However, the authors acknowledged several study limitations. Methods for diagnosing MG varied between the studies reviewed, including an assay of acetylcholine receptor antibodies, pharmacological data to indicate a prescription for pyridostigmine, which is only used in MG, and the use of specialists—such as neurologists and ophthalmologists—to make the diagnosis. Study populations varied as well, with data from affluent areas pivotal to one study, while another emphasized data from larger cities.

Still, the authors said their findings highlight DRB1*04.04 and DRB1*03 as a possible cause of the disease. “Screening for these alleles, particularly in Northern Europe, may help identify individuals susceptible to MG,” they concluded.

References

1. Kurian M, Khera N. Correlation between the prevalence of myasthenia gravis and the frequency of class II human leucocyte antigen alleles in various geographical locations around the world. Cureus. 2024;16(9):e69791. doi:10.7759/cureus.69791

2 Tereshko Y, Kurnianto A, Retnaningsih, Andhitara Y, Ardhini R, Budiman J. The relationship between myasthenia gravis and COVID 19: a systematic review. Egypt J Neurol Psychiatr Neurosurg. 2022;58(1):83. doi:10.1186/419833-022-00516-3