Association of a Low-Frequency Variant in<i>HNF1A</i>With Type 2 Diabetes in a Latino Population
Authors: Karol Estrada, Ingvild Aukrust, Lise Bjørkhaug, Noël P. Burtt, Josep M. Mercader, Humberto García-Ortiz, Alicia Huerta-Chagoya, Hortensia Moreno-Macías, Geoffrey Walford, Jason Flannick, Amy L. Williams, María J. Gómez-Vázquez, Juan C. Fernandez-Lopez, Angélica Martínez-Hernández, Federico Centeno-Cruz, Elvia Mendoza-Caamal, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Emilio J. Córdova, Xavier Soberón, María E. González-Villalpando, E. Henderson, Lynne R. Wilkens, Loic Le Marchand, Olimpia Arellano-Campos, Maria L. Ordóñez-Sánchez, Maribel Rodríguez-Torres, Rosario Rodríguez-Guillén, Laura Riba, Laeya A. Najmi, Suzanne B.R. Jacobs, Timothy Fennell, Stacey Gabriel, Pierre Fontanillas, Craig L. Hanis, Donna M. Lehman, Christopher P. Jenkinson, Hanna E. Abboud, Graeme I. Bell, Maria L. Cortes, Michael Boehnke, Clicerio González-Villalpando, Lorena Orozco, Christopher A. Haiman, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, David Altshuler, Pål R. Njølstad, Jose C. Florez, Daniel G. MacArthur
Journal: JAMA (2014)

<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.