Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population

JAMA. 2014 Jun 11;311(22):2305-14. doi: 10.1001/jama.2014.6511.

Abstract

Importance: Latino populations have one of the highest prevalences of type 2 diabetes worldwide.

Objectives: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships.

Design, setting, and participants: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays.

Main outcome and measures: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function.

Results: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19).

Conclusions and relevance: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genotype
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Hispanic Americans / genetics
  • Humans
  • Male
  • Mexico
  • Middle Aged
  • Mutation, Missense
  • Sequence Analysis, DNA
  • United States

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 3