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

ABSTRACT: Latino populations have one of the highest prevalences of type 2 diabetes worldwide.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.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.Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function.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-? (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).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.

SUBMITTER: SIGMA Type 2 Diabetes Consortium

PROVIDER: S-EPMC4425850 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Estrada Karol K Aukrust Ingvild I Bjørkhaug Lise L Burtt Noël P NP Mercader Josep M JM García-Ortiz Humberto H Huerta-Chagoya Alicia A Moreno-Macías Hortensia H Walford Geoffrey G Flannick Jason J Williams Amy L AL Gómez-Vázquez María J MJ Fernandez-Lopez Juan C JC Martínez-Hernández Angélica A Jiménez-Morales Silvia S Centeno-Cruz Federico F Mendoza-Caamal Elvia E Revilla-Monsalve Cristina C Islas-Andrade Sergio S Córdova Emilio J EJ Soberón Xavier X González-Villalpando María E ME Henderson E E Wilkens Lynne R LR Le Marchand Loic L Arellano-Campos Olimpia O Ordóñez-Sánchez Maria L ML Rodríguez-Torres Maribel M Rodríguez-Guillén Rosario R Riba Laura L Najmi Laeya A LA Jacobs Suzanne B R SB Fennell Timothy T Gabriel Stacey S Fontanillas Pierre P Hanis Craig L CL Lehman Donna M DM Jenkinson Christopher P CP Abboud Hanna E HE Bell Graeme I GI Cortes Maria L ML Boehnke Michael M González-Villalpando Clicerio C Orozco Lorena L Haiman Christopher A CA Tusié-Luna Teresa T Aguilar-Salinas Carlos A CA Altshuler David D Njølstad Pål R PR Florez Jose C JC MacArthur Daniel G DG

JAMA 20140601 22

<h4>Importance</h4>Latino populations have one of the highest prevalences of type 2 diabetes worldwide.<h4>Objectives</h4>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.<h4>Design, setting, and participants</h4>Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 ...[more]

PMID: 24915262

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Project description:BackgroundC-reactive protein (CRP), a biomarker of inflammation, has been associated with increased risk of developing cardiovascular disease. Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1alpha have been associated with plasma CRP in predominantly European Caucasian samples. HNF1A might therefore have an impact on vascular disease and diabetes risk that is mediated by CRP. In an Aboriginal Canadian population, a private polymorphism, HNF1A G319S, was associated with increased prevalence of type 2 diabetes. However, it has not been investigated whether this association is mediated by CRP. We aimed to investigate whether CRP was mediating the association between HNF1A G319S and type 2 diabetes in an Aboriginal Canadian population with a high prevalence of diabetes.MethodsA total of 718 individuals who participated in a diabetes prevalence and risk factor survey were included in the current analysis. Participants were genotyped for HNF1A G319S. Fasting plasma samples were analyzed for CRP. Fasting plasma glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes.ResultsThe prevalence rate of type 2 diabetes was 17.4% (125/718) using the 1999 World Health Organization definition and was higher among S319 allele carriers compared to G/G homozygotes (p < 0.0001). Among participants without type 2 diabetes, CRP levels were higher among G/G homozygotes (1.64 [95% confidence interval 1.35-2.00] mg/l) than in S319 carriers (1.26 [1.04-1.54] mg/l) (p = 0.009) after adjustment for age, sex, 2-h post-load glucose, waist circumference, and serum amyloid A. CRP levels were elevated among those with diabetes after similar adjustment (4.39 [95% confidence interval 3.09-6.23] and 4.44 [3.13-6.30] mg/L, respectively), and no significant difference in CRP was observed between S319 carriers and non-carriers (p = 0.95).ConclusionsCRP levels were lower in S319 allele carriers of the HNF1A gene compared to non-carriers among individuals without diabetes, but this difference was not present among those with diabetes, who uniformly had elevated CRP levels. Therefore, while HNF1A appears to influence CRP concentrations in the non-diabetic state, chronic elevation of CRP is unlikely mediating the association between the HNF1A polymorphism and the high prevalence of type 2 diabetes in this Aboriginal population.

Dataset Information

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

Publications

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

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