Researchers at Oxford Population Health contributed to a study that has demonstrated that people who carry specific (protein-truncating) variants in the MAP3K15 gene are 30% less likely to develop diabetes, and that they have lower levels of glucose in their blood, irrespective of their body mass index. This suggests that these variants may protect against diabetes even in people who are obese and more likely to develop type 2 diabetes. The results suggest that MAP3K15 provides a new target for developing therapies to prevent and treat diabetes.
Diabetes is one of the fastest-growing diseases worldwide and is projected to affect 700 million people globally by 2045. It is currently the leading cause of disease of small and large blood vessels, and can lead to kidney failure, blindness, heart disease, and lower limb amputations. Diabetes is broadly categorised into type 1 and type 2, and other rarer forms, all of which share the adverse health consequences of persistently elevated blood glucose.
The researchers initially performed analyses on exomes (the ~2% of the genome that encodes proteins) from 454,796 UK Biobank participants to detect genetic associations with diabetes. The study was then replicated in 96,811 participants of admixed American ancestry in the Mexico City Prospective Study (MCPS), and 260,405 people of Finnish descent in the FinnGen study.
- In the UK Biobank population, people who were unable to make the MAP3K15 protein were 35% less likely to develop diabetes and had lower blood glucose levels, independent of body mass index.;
- The findings were replicated in the data from MCPS participants, which also showed that the protective effect of the MAP3K15 variants was stronger in individuals who do not carry the SLC16A11 risk haplotype (a group of variants that are inherited together from one parent) that affects around 20% of people of Mexican descent;
- The results from the FinnGen study demonstrated that a specific variant (the Arg1122* protein-truncating variant of MAP3K15), which is considerably more prevalent in people of Finnish descent compared to non-Finnish Europeans, was associated with decreased risk of both type 1 and type 2 diabetes;
- The protective effects were strongest against type 2 diabetes overall but protection against type 1 diabetes was also shown in the UK and Finnish populations;
- There were no adverse associations between the variants and diseases such as coronary artery or cardiovascular disease, suggesting that this gene could be a safe and promising new target for managing diabetes.
Jonathan Emberson, Professor of Medical Statistics and Epidemiology at Oxford Population Health, said ‘The data indicate that people who have low levels, or a total lack, of MAP3K15 are otherwise healthy, indicating that MAP3K15 is likely to be a safe target for the prevention, and possibly treatment, of both type 1 and type 2 diabetes. Further research is needed to see whether this is the case, but the current findings suggest that a new medicine targeting MAP3K15 could potentially help millions of people around the world manage their diabetes, as well as help prevent diabetes among those at greatest risk.’
The results are published in Science Advances.