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The prevalence of type 2 diabetes among Latin Americans is approximately twice as high as among Europeans and White Americans. A new study in the journal JAMA from an international team of researchers known as the SIGMA Diabetes Consortium has uncovered a genetic variant that confers a substantially increased risk of type 2 diabetes and is primarily observed in Latin American patients but not others. The variant is in a gene called hepatocyte nuclear factor 1-a (HNF1A); this is the gene responsible for a rare type of diabetes called maturity onset diabetes of the young type 3 (MODY3). The finding sheds light on the population genetics of type 2 diabetes among Latin Americans and may have implications for screening programmes and tailored therapies.

In this study, the research team performed a technique called exome sequencing, which analyses the parts of the genome that encode proteins, on samples from 3756 Mexican and US Latino individuals with or without type 2 diabetes. The results indicated that a rare variant in HNF1A was associated with prevalence of type 2 diabetes. When this p.E508K variant was explored further in a multi-ethnic set of 14276 patients, it was observed that it occurred only in Latino patients and was associated with type 2 diabetes. Corresponding author Jose Florez explained: "We've identified a genetic risk factor that is present in roughly 2 percent of Mexicans with type 2 diabetes, and its effects are substantial — raising a person's risk of developing the disease fivefold." Functional studies on the variant revealed that it had reduced activity compared to wild type.

The role of the p.E508K variant is new but its effects appear to be less severe than the situation in MODY, in which the HNF1A function is fully disabled. MODY usually emerges earlier in life than type 2 diabetes whereas the new variant did not appear to be associated with earlier age of onset. It appears that the newly identified variant spares some HNF1A functionality. MODY is often responsive to an inexpensive class of drugs called sulfonylurea, being much more sensitive to these drugs than to the first-line type 2 diabetes drug metformin. Therefore, this study raises the question whether type 2 diabetes associated with p.E508K may also be effective. For now, the research team are cautious about therapeutic implications, stressing the necessity for more studies. Study co-author Teresa Tusie-Luna concludes: "This is an outstanding discovery — one that helps explain the epidemic rates of type 2 diabetes in Latin American populations…But we must be mindful that, while the finding is associated with high levels of risk for the disease, we still do not know how the mutation behaves and if there is a specific therapeutic method can be safely applied in the clinic for individuals that carry the mutation. There is much more we need to learn."

Sources

The SIGMA Type 2 Diabetes Consortium (2014). Association of a Low-Frequency Variant in HNF1A with Type 2 Diabetes in a Latino Population. JAMA. 2014; 311(22):2305-2314. doi:10.1001/jama.2014.6511

Press release: JAMA, available from http://www.eurekalert.org/bysubject/biology.php