Sunday , November 19 2017
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High Prevalence of Type 2 Diabetes in Latino Populations Associated with Low Frequency Variant in HNF1A

HNF1A is also the gene responsible for (maturity onset diabetes of the young type 3 (MODY3), a rare monogenic cause of diabetes….

According to statistics gathered between 1999 and 2002, 10% of Mexican Americans were living with type 2 diabetes as opposed to only 5.2% of white Americans. Diabetes is one of the leading causes of death in Mexico with an estimated 14.4% of the adult population diagnosed with the disease in 2006.

This study was performed as part of the Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes Consortium, which is trying to characterize the genetic basis of type 2 diabetes in Latino populations based on populations from 4 previous studies. Diagnosis of type 2 diabetes used in the study was according to criteria laid out by the American Diabetes Association. Only 2% of study participants had type 2 diabetes onset prior to age 25 and 81% of participants had a BMI greater than 25.

Whole-exome sequencing was performed on the DNA samples of 3,756 individuals of Latino descent between the years 1993 to 2013. Ancestry was determined by self-report and confirmed with genotype data. Of these, 1,794 were living with type 2 diabetes. The primary endpoint was presence of the disease.

What the study found was that a single rare missense variant, p.E508K, could be associated with type 2 diabetes in hepatocyte nuclear factor 1-alpha (HNF1A) which is the gene responsible for MODY3 (maturity onset diabetes of the young type 3). MODY is a monogenic cause of diabetes and usually presents at a younger age (<25) in non-obese patients. This variant was seen in 2.1% of the study participants with type 2 diabetes and only 0.36% of those without the disease.

The results of this study and the association of the p.E508K variant with type 2 diabetes could have clinical implications. Approximately 4 of every 1000 Latinos carry the variant and these individuals have a 5-fold increase in risk for development of type 2 diabetes. It is known that patients with MODY3 are sensitive to sulfonylureas and have a 5-fold higher response than when treated with metformin, which is currently the first line drug of choice in type 2 diabetes. If this was shown to be the case for carries of the p.E508K variant, sulfonylureas could become the treatment of choice in those who carry the variant.

Practice Pearls:
  • 10% of Mexican Americans are living with type 2 diabetes as opposed to only 5.2% of whites.
  • A single rare missense variant, p.E508K, in hepatocyte nuclear factor 1-alpha (HNF1A) is associated with an increased prevalence of type 2 diabetes in Latino populations.
  • Sulfonylureas may become the drug of choice in treatment of patients with type 2 diabetes who show evidence of the variant.

Estrada, Karol, PhD, Aukrust, Ingvild PhD, Bjorkhaug, Lise, PhD, et al. Association of a Low-Frequency Variant in HNF1A with Type 2 Diabetes in a Latino Population. JAMA. 2014; 311(22)2305-2314