<h3>Importance</h3> Latino populations have one of the highest prevalences of type 2 diabetes worldwide. <h3>Objectives</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Main Outcome and Measures</h3> Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. <h3>Results</h3> A single rare missense variant (c.1522G&gt;A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61;<i>P</i> = 4.4 × 10<sup>−7</sup>) in hepatocyte nuclear factor 1-α (<i>HNF1A</i>), 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;<i>P</i> = .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 (<i>P</i> = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (<i>P</i> = .19). <h3>Conclusions and Relevance</h3> Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene<i>HNF1A</i>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.

Association of a Low-Frequency Variant inHNF1AWith Type 2 Diabetes in a Latino Population