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Rare gene variant linked to type 2 diabetes in Latino population
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A single, low-frequency variant identified in a gene as being associated with type 2 diabetes in Latino populations may hold potential for screening and other therapeutic modifications, according to research published in JAMA.
“We have identified a genetic variant that increases risk of type 2 diabetes fivefold and is present mostly in Latinos, with a frequency near 2% in Mexicans affected with the disease,” Jose C. Florez, MD, PhD, of the Center for Human Genetic Research, Massachusetts General Hospital, told Endocrine Today. “It illustrates the need to conduct genetic studies in diverse populations.”
Using whole-exome sequencing, the abnormality was detected in hepatocyte nuclear factor 1-alpha (HNF1A), responsible for maturity-onset diabetes of the young (MODY), by scientists in the Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes Consortium.
This discovery, Florez said, “adds to the field by expanding the genetic architecture of type 2 diabetes beyond what has been discovered in European populations.”
Jose C. Florez
Karol Estrada, PhD, of the Broad Institute of Harvard and MIT, and investigators with the consortium conducted the genetic analysis using DNA samples from 3,756 Mexican and US Latino individuals (1,794 with type 2 diabetes; 1,962 without diabetes) recruited between 1993 and 2013. The researchers performed sequencing on part of the genome to capture common and rare variants in protein-coding regions of the genes. One variant was further tested for type 2 diabetes links in large multiethnic data sets that included 14,276 participants.
A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (OR=5.48; 95% CI, 2.83-10.61) in HNF1A. The variant was seen in 2.1% of participants with type 2 diabetes and 0.36% of participants without.
In the multiethnic data sets, the p.E508K variant was only observed in Latino patients (n=1,443 with type 2 diabetes; 1,673 without) and correlated with type 2 diabetes (OR=4.16; 95% CI, 1.75-9.92).
Experimental assays found the HNF1A protein encoding the p.E508K variant reduced transactivation activity of its target promoter compared with a wild-type protein.
No significant differences in clinical characteristics were observed between carriers and noncarriers of the p.E508K mutation with type 2 diabetes, including age at onset.
“This shows that other variants in genes that cause rare, monogenic forms of diabetes (MODY) can also influence type 2 diabetes, that the clinical features at diagnosis are not different from those of type 2 diabetes,” Florez said. “It suggests that those affected might be better treated with the drug class that works best in MODY, such as sulfonylureas, although this point has to be proven in a properly designed clinical trial.” — by Allegra Tiver
For more information:
Florez can be reached at the Center for Human Genetic Research, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: jcflorez@mgh.harvard.edu.
Disclosure: Please see study for full list of researchers’ financial disclosures
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