Rare variants of a single gene seem to make patients more susceptible to multiple diseases.
Differences in the sequence of a single gene may be partly responsible for causing around 2% of relatively common autoimmune disorders including diabetes and arthritis.
The gene codes for an enzyme called sialic acid acetylesterase (SIAE) that regulates the immune system's B cells — the cells responsible for producing antibodies against foreign invaders. In 24 of 923 people with conditions such as Crohn's disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, the gene was present in a variant form.
For the past five years, genome-wide screens of large groups of patients have searched for commonly occurring gene variants associated with complex diseases that are unlikely to have a single genetic cause. Although many such variants have been identified, they explain little in terms of disease susceptibility. More recently, scientists have begun to wonder whether rare variants may better account for the genetic underpinnings of such diseases.
"It's still very much a question mark" whether rare variants will contribute to complex and relatively common disorders, says Jay Shendure, a genomicist at the University of Washington in Seattle who was not involved in the study. "But studies like this show that there is something to be found."
I think this is an absolutely seminal paper. ,
Shiv Pillai of Harvard Medical School in Boston, Massachusetts, and his colleagues had previously found that deactivating the Siae gene in mice leads to a condition similar to the autoimmune disease systemic lupus erythematosus1. They decided to resequence the gene in humans to probe its link to autoimmune diseases, and identified several variants in people with autoimmune disorders. Healthy people occasionally had variants of the gene as well, but when the researchers tested the different variants, they found that those in people with autoimmune diseases tended to disrupt the enzyme's function, whereas those in healthy individuals did not.
"If you divide the findings into whether the alleles are defective or not, then the effect is very striking," says Shendure. The researchers found there were nine times as many defective variants in individuals with autoimmunity.
Shendure says that conducting such functional studies after identifying variants is crucial — but not easy. There are great functional assays for SIAE, he says, but many genes, even well-studied ones such as the breast-cancer gene BRCA1, which his lab studies, don't have them. "There aren't functional assays for every gene, nor is it easy to establish functional assays for every gene."
Pillai and his group think that SIAE and other genes in the same pathway stop B cells from making antibodies against host tissue. B cells that react strongly to host tissue are generally destroyed in the bone marrow, but weakly self-reactive B cells can sometimes become strongly self-reactive, setting the scene for an autoimmune reaction. In mice, the researchers found, SIAE keeps that process in check — explaining how mutations in the gene or others in the same pathway could increase susceptibility to autoimmune disease. Although relatively few people in the current study, published online in Nature today2, carried the defective variants for SIAE, Pillai suspects that many more harbour mutations in closely interacting genes.
"I think this is an absolutely seminal paper," says Judy Cho, an immunogeneticist at Yale University in New Haven, Connecticut. The strength of it, she adds, is that it proposes a very specific hypothesis — namely, the role of the sialic acid pathway in autoimmune disease — that can now be tested.
Pillai's group has homed in on one specific gene, but as gene sequencing gets cheaper, he says that researchers will be able to identify rare variants by sequencing whole exomes — the roughly 1% of the genome carrying instructions to build proteins — and comparing them between people with disease and controls. "We have looked at one gene, and there are 20,000 genes," says Pillai. "Exome sequencing will give us the opportunity to look at them all."
But Shendure and Cho say that they're not sure whether statistically, exome sequencing — without hypotheses to narrow down the search — could have fished out the SIAE gene. "There are several hundred novel polymorphisms in the genome," says Cho. "So how do you pick this needle out of the haystack"?
Cariappa, A. et al. J. Exp. Med. 206, 125-138 (2009).
Surolia, I. et al. Nature advance online publication doi:10.1038/nature09115 (2010).
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Katsnelson, A. Gene linked to autoimmune diseases. Nature (2010). https://doi.org/10.1038/news.2010.300