title: Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.
abstract: OBJECTIVE
  Latino populations have one of the highest prevalences of type 2 diabetes worldwide.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston3Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008297:Male; D008800:Mexico; D008875:Middle Aged; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D014481:United States
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha