Science Advances: Exome sequencing studies discover potential therapeutic targets for diabetes

Through a large-scale exome sequencing association study, researchers began to use MAP3K15 as a potential target for diabetes treatment
.

Researchers at AstraZeneca and the University of Melbourne analysed 412,000 people in the UK Biobank and found that recessive carriers of the nonsynonymous variant of MAP3K15 were 30% less likely to develop diabetes and had reduced glycosylated haemoglobin levels
.
They repeated this finding
in two other datasets.
The study was published Nov.
16 in the journal Science Advances
.

It is estimated that by 2045, 700 million people worldwide will be living with diabetes
.
The researchers believe that their results suggest that MAP3K15 may represent a therapeutic target for diabetes and is worth exploring
further in humans.

The researchers focused their analysis on individuals in the UK biobank who self-reported having diabetes
.
They studied associations between more than 18,000 genes and their phenotypes, including European ancestry analysis and pan-ancestry analysis
.

In European ancestry analysis, four protein-coding genes are associated with at least one diabetes phenotype, three of which have been previously reported
.
The recessive protein truncation variant of the fourth gene, MAP3K15, was significantly associated with
a reduced likelihood of diabetes formation.
In addition, carriers of these MAP3K15 variants also had lower HbA1c levels and non-fasting blood glucose levels
.
In pan-ancestry analysis, these MAP3K15 variants were equally protective against diabetes
.

The researchers then repeated their analysis
using data from the Mexico City Prospective Study and the Finnish Genomics Study (FinnGen).
They noted some nuances in the effects of the MAP3K15 variant on the two populations
.

For example, if an individual in Mexico or Latin America carries a variant of the SLC16A11 gene, the MAP3K15 variant has no protective effect on the individual
.
In other words, treatments targeting MAP3K15 may not
be as effective as effective in individuals carrying SLC16A11 mutations.
In addition, the researchers noted that the protein truncated variant Arg1122* of MAP3K15 was more common
in Finns.
They noted that this variant provided significant protection
against both type 1 and type 2 diabetes.

In the phenotypic group analysis, the researchers examined whether MAP3K15 was associated with
other diabetes or metabolic syndrome traits, such as obesity and cholesterol levels.
They found that the effects of the MAP3K15 variant were independent of BMI and were only associated with a decrease in glucose and not with other metabolites
.
They also noted that MAP3K15 is expressed not only in the adrenal glands, but also in organs such as the pancreas
.

The researchers say their results suggest that MAP3K15 may be a target for the treatment of diabetes
.
They also noted that approximately 0.
6% of men in the UK biobank lacked functional MAP3K15 without any apparent problems, and that an association analysis found no association between the MAP3K15 variant and an adverse clinical phenotype, supporting it as a therapeutic target
.

Original search

Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes

SCIENCE ADVANCES

DOI: 10.
1126/sciadv.
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