Rare and Once-ignored Mutations May Contribute to Lupus, Study Finds

Certain rare gene mutations, previously ignored, appear to contribute substantially to the development of lupus, new research found, pointing to the potential for targeted therapies for the condition.

The study, “Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus,” was published in Nature Communications.

The cause of lupus has long been a mystery. It’s assumed to be due to some combination of environmental and genetic factors, but figuring out precisely what those factors are has proved a challenge.

In this study, researchers used sequencing — either of the whole genome or of just its protein-coding parts, called the exome — to identify rare genetic variants in people with lupus (133 people) or healthy controls (97 people).

Many rare mutations in genes thought to be related to lupus were identified in both the lupus and the control groups — although rates were typically significantly higher in the lupus cohort.

“Until now, it was thought that these rare variants played a negligible role in human autoimmunity and related autoimmune diseases,” Simon Jiang of the Australian National University and a study author, said in a press release. “We’ve shown how most lupus patients harbor those so-called rare gene variants.”

Lupus patients more commonly had mutations in the genes BLK and BANK1, both involved in the function of B-cells, which make antibodies and, as such, play a key role in the disease’s development and progression.

More in-depth investigations found that some of the identified variants led to molecular changes that caused immune cells to release more of a molecule called interferon, which is a powerful activator of inflammation. In a mouse model of lupus, introducing one of the variants into immune cells made them more reactive to immune reaction-inducing stimuli.

This suggests that these variants lead to greater inflammation, at the least, so it’s logical to suppose they could help to drive autoimmune diseases like lupus.

“These rare gene variants cause immune cells to no longer work properly,” Jiang said. “When the cells no longer work, your immune system struggles to distinguish viruses and bacteria from self, leading to lupus.”

Of course, the picture is far from entirely clear. For starters, none the individual variants come close to explaining lupus: the most frequently mutated gene, BLK, was mutated in less than 11% of lupus patients and in about 7% of healthy controls.

Furthermore, some lupus patients didn’t have any detected mutations that were deemed relevant. So, while one of the identified mutations may slightly increase the odds of lupus in an individual, none of them — not even all of them together — could be the “cause” of lupus.

The researchers tested only a few variants in specific genes that were deemed to be of interest. Most of those identified have not undergone rigorous scientific scrutiny to see whether there is validity to the idea that they contribute to lupus.

Still, this research does support the idea that very rare genetic changes could in some cases play a key, and overlooked, role in this autoimmune disease.

And, because mutations in a given individual can be determined relatively quickly and easily, “There is huge potential for targeted treatment” and for better diagnostic tests, Jiang said.