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Canker Sore Risk Influenced by Nearly 100 Genetic Variants, GWAS Reports

NEW YORK (GenomeWeb) – Researchers led by a team at the University of Bristol in the UK have uncovered nearly 100 genetic variants that influence the risk of developing mouth ulcers, also known as canker sores.

About a quarter of young adults and an even higher portion of children develop canker sores, and while some result from trauma or autoimmune or inflammatory conditions, the origins of other sores are unclear. Previous studies, though, have suggested a genetic influence.

The researchers conducted a genome-wide association study that identified 97 common genetic variants that influence canker sore risk. As they reported in Nature Communications today, they further found that these variants were enriched in immune system-related genes, particularly those involved in the regulation of T cells, and that many of these genes are in pathways that are targeted by existing drugs.

"Currently, there are few satisfactory drug treatments for mouth ulcers as current medication options are non specific and can lead to side effects," co-first author Tom Dudding, a research fellow in the Bristol Medical School, said in a statement.

He and his colleagues conducted a GWAS using data on 461,106 individuals from the UK Biobank that tied more than 7,000 variants to risk of developing mouth ulcers. They whittled that list down to 97 independent lead variants, which they then tested in a cohort of 355,744individuals from 23andMe. All 97 variants exhibited directional consistency and similar effect sizes in both cohorts.

They likewise examined these variants in three other cohorts with more clearly defined clinical phenotypes to find that 24 of the 97 lead variants showed a consistent direction of effect in all cohorts.

After a meta-analysis of the UK Biobank and 23andMe cohorts, the signal with the strongest evidence for association with canker sores was a common variant near IL12A on chromosome 3. Other top variants were in IL10, near CCR3, and in CCRL2. The researchers also identified variants within the HLA region that were linked to an increased risk of developing mouth ulcers.

Using the DEPICT tool that prioritizes likely causal genes, they homed in on chemokines or chemokine receptors as plausible candidate genes, such as IL12A or IL12B.

These and other analyses of the signals the researchers reported highlight a role for the immune system in mouth sore risk. For instance, a DEPICT-based gene set analysis uncovered an enrichment of canker sore-related loci among genes involved in T cell regulation, including in alpha-beta T cell differentiation and T cell activation. Other analyses using the S-PrediXcan tool that predicts gene expression from genotype data found evidence that IL12A, SCHIP1, and IL10 influence canker sore risk.

According to the researchers, the variants they uncovered that appear to have the largest effect on mouth ulcer risk encourage a Th1-type immune response. This, they said, was a biologically plausible mechanism, as well as in line with previous reports in the literature and with clinical practice.

Additionally, to characterize the signal they found near HLA-B, the researchers conducted an analysis of imputed haplotypes, which uncovered two dozen haplotypes linked to canker sores. The strongest finding was at DRB1*0103, an uncommon haplotype of HLA-DRB1 that encodes the beta chain of the HLA-DR heterodimer, which itself is a T cell receptor ligand.

Existing drugs target some of these genes and pathways, the researchers found. One, dubbed ustekinumab, is an antibody against the IL12 protein. It is used to treat conditions like psoriasis and Crohn's disease and could be repurposed for canker sores, they said.

"There is the potential that drugs like these could be used to treat mouth ulcers, although further work is required to demonstrate this," Dudding said.