Variations in Immune System Gene Linked to Late-onset MG Risk, Meta-analysis Suggests

Variations in the gene DRB1 are associated with different risks of developing late-onset myasthenia gravis (LOMG), a recent meta-analysis suggests.

This finding may lead to the identification of promising biomarkers for LOMG risk, the researchers said.

The analysis, titled “The associations of HLA-DRB1 gene polymorphisms with late-onset myasthenia gravis: a meta-analysis,” was published in Neurological Sciences. 

The major histocompatability complex (MHC) is a group of genes that code for proteins that play a critical role in the body’s immune system, helping recognize potential threats. The MHC also is called human leukocyte antigen, or HLA. The exact sequence of the MHC’s genes vary greatly from person to person and can have important biological effects. For instance, the differences can affect whether or not a transplanted organ is rejected.

Because of their importance in the immune system, it makes a certain sense that polymorphisms — variants of a particular DNA sequence — in MHC genes might affect an individual’s risk for autoimmune diseases, such as MG. Indeed, some variations in DRB1, a MHC gene, have been linked with different risks of developing LOMG.

However, studies have found conflicting results regarding a link between DRB1 — also called HLA-DRB1 — variations and LOMG risk.

To learn more, the researchers conducted a meta-analysis, which involves synthesizing data from multiple previously published studies in order to draw broader conclusions than any of the studies could alone. The team combed through the existing scientific literature to identify studies that assessed the relationship between DRB1 genetic variations and late-onset MG risk.

In total, the analysis included 11 studies, with data on 5,513 people — 947 LOMG patients and 4,566 healthy people (controls). As its name suggests, LOMG is defined as myasthenia gravis that manifests later in life, though there isn’t a universally agreed-upon cutoff age. For this meta-analysis, age 40 was used as the cut-off.

The included studies were published between 1998 and 2019, and were conducted in multiple countries in Asia and Europe. On the Newcastle-Ottawa Scale, which measures the quality of a study, all were rated 6 or 7 out of 9, suggesting good quality.

In all the studies, the participants’ DRB1 genetic variations were determined using a blood test. The researchers then calculated the relative risk of LOMG in people with particular variations. While there are hundreds of known DRB1 variants, and not every study analyzed every one, the investigators nonetheless were able to identify those variants that had been assessed by multiple studies. That allowed broad conclusions to be drawn from the data.

For instance, a variant named DRB1 07 — or HLA-DRB1 07 allele — was associated with a significant increase in LOMG risk, by an estimated 83%, based on data from five studies. In a subgroup analysis by ethnicity, the higher risk remained significant among Asians — with an increased LOMG risk estimated at 215% — but not Caucasians. Other ethnicities were not discussed, presumably due to low sample sizes.

Based on data from all participants in six studies, the variant DRB1 04 was not associated with an increased risk of late-onset MG. The same lack of increased risk for the participants in total was found for DRB1 14, based on data from five studies.

However, an ethnicity-based subgroup analysis revealed a significantly increased risk among Caucasians — by 221% for DRB1 04, and 282% for DRB1 14 — but not for Asians.

The variant DRB1 0403 also was associated with a significantly increased LOMG risk, by over seven-fold. However, this variant was only analyzed in one of the included studies, making the evidence for this finding somewhat less strong.

Two variants, DRB1 0301 and DRB1 1301, each of which were assessed in three studies, were associated with a significantly lower risk of late-onset MG.

For all other variants analyzed, the results did not indicate a statistically significant association with LOMG risk, one way or the other. Ethnicity analyses similarly revealed no significant associations.

Of course, these results don’t necessarily mean that no such association exists — some genetic variations may have tiny effects that can only be reliably detected in datasets numbering in the millions. However, this analysis, with the data available, did not provide evidence for the existence of such associations.

The researchers did, however, single out one other allele, the DRB1 1501. They noted that this allele “may still be a potential risk factor for the LOMG although further investigations are needed to be conducted in different ethnic populations.”

“In summary, our meta-analysis demonstrated that HLA-DRB1 07 and 0403 alleles were risk factors for LOMG while the HLA-DRB1 0301 and 1301 alleles were protective factors for LOMG,” the team said.

However, these results shouldn’t be boiled down as certain variants being “good” while others are “bad,” the researchers said. The science here is much more complicated and nuanced than that. For instance, DRB1 0301 was associated with a decreased LOMG risk, but this same variation has been linked with a significantly higher risk of early-onset breast cancer.

Additional research will be needed to fully understand the intricacies of how DRB1 variations affect human health, including the mechanisms by which they may affect late-onset MG risk, the scientists concluded.