1. Publications

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

SIGMA Type 2 Diabetes Consortium; 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, Silvia Jiménez-Morales, 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.
JAMA.. 2014-06-11;311(22):2305-14.
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.
Datasets
DSR722RJX