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Exome Sequencing Study Identifies Potential Treatment Target for Diabetes

NEW YORK — Through a large exome sequencing association study, researchers have homed in on MAP3K15 as a potential therapeutic target for managing diabetes.

In their analysis of about 412,000 individuals from the UK Biobank, researchers led by Slavé Petrovski from AstraZeneca and the University of Melbourne found that recessive carriers of nonsynonymous variants in MAP3K15 were 30 percent less likely to develop diabetes and had lower levels of glycosylated hemoglobin, findings they replicated in two other large datasets. Their work was published this week in Science Advances.

In combination with additional analyses, the researchers said their findings indicate that MAP3K15 could represent a treatment target for diabetes, which is expected to affect 700 million people worldwide by 2045. "The lack of association between recessive variation in MAP3K15 and any deleterious phenotypes suggests that pharmacologically modulating MAP3K15 may be safe and worthwhile to explore in humans," Petrovski and colleagues wrote in their paper.

The researchers focused their analysis of UK Biobank data on individuals who had self-reported unspecified diabetes, non-insulin-dependent diabetes, insulin-dependent diabetes, and strict insulin-dependent diabetes. They examined associations between more than 18,000 genes and these phenotypes in UKB participants of European ancestry and in a pan-ancestry analysis.

In the European ancestry analysis, four protein-coding genes were associated with at least one of those diabetes phenotypes, three of which have been reported previously. Recessive protein-truncating variations in the fourth, MAP3K15, were significantly associated with reduced odds of developing diabetes. Further, carriers of these MAP3K15 variants also had lower HbA1c levels and nonfasted blood glucose levels. These MAP3K15 variants were likewise protective against diabetes in the pan-ancestry analysis.

The researchers then replicated their analysis using data from Admixed Americans from the Mexico City Prospective Study and from FinnGen. However, the researchers noted some nuances in the effects of the MAP3K15 variants within these two populations.

For instance, diabetes among individuals of Mexican or Latin American genetic ancestry is often linked to variants in the SLC16A11 gene. Here, the researchers noted that though MAP3K15 variants were associated with a reduced risk of developing diabetes among individuals without that risk-related SLC16A11 gene variants, they were not protective among individuals with SLC16A11 gene variants. This suggests that if treatments targeting MAP3K15 were developed, they could be less effective among individuals with SLC16A11 gene variants.

Meanwhile, the researchers noted that the protein-truncating variants in MAP3K15 variant Arg1122* was more common among Finns. This variant, they noted, provided significant protection against both type 1 and type 2 diabetes in this population, which has the highest global rate of childhood type 1 diabetes, making it better powered to detect that association.

In phenome-wide analyses, the researchers examined whether MAP3K15 is linked to other diabetes- or metabolic syndrome-associated traits such as obesity and cholesterol levels. The effect of the MAP3K15 variants, though, was independent of BMI and was only associated with reduced glucose and not any other metabolites. They additionally noted that MAP3K15 is expressed in the adrenal glands but also in other organs, like the pancreas and particularly among the islet cell populations.

This and other findings suggest that MAP3K15 may reduce the risk of type 1 and type 2 diabetes by affecting insulin sensitization.

Further, researchers said that their results indicated that MAP3K15 could be a target for managing diabetes. They also noted that about 0.6 percent of men in the UK Biobank lack a functional MAP3K15 without any apparent issues, as they are a relatively healthy cohort, and that an association analysis found no ties between MAP3K15 variants and adverse clinical phenotypes, supporting its potential as a treatment target.

"Our results suggest that pharmacologically targeting MAP3K15 could be an orthogonal approach to managing diabetes outside the traditional arsenal," Petrovski and colleagues wrote.