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

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.

Diabetes in Population Isolates: Lessons from Greenland

“…In the Mexican and MexicanAmerican population, variants in SLC16A11, which are common in these populations, but rare in Europeans, were found to be associated with a modest increase in T2D prevalence [27]. Furthermore, a whole exome sequencing-based study identified a rare missense variant, which has a high impact on T2D (OR ~5) [28]. This variant is located in HNF1A, a gene in which damaging mutations are known to cause MODY subtype 3 [29].…”

“…This variant is located in HNF1A, a gene in which damaging mutations are known to cause MODY subtype 3 [29]. The variant was also observed at an allele frequency of 2.1% in T2D cases and 0.36% in control individuals in the Mexican population [28]. In comparison, it was found only in 2 of 32,990 nonFinnish Europeans sequenced as part of the Exome Aggregation Consortium [30].…”

When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

“…The association of the p.E508K variant in HNF1A with a T2D phenotype was replicated in the T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) Latino group and in a de novo genotyping data set from selfidentified indigenous Mexicans (DMS2) (OR 4.16; 95% CI 2.93-8.38). There was no evidence of p.E508K in exomes from large multi-ethnic data sets, other than in Latino samples from these consortia cohorts, confirming its exclusivity to Mexican/Mexican American ethnic groups [78].…”

“…This study was among the first systematic, high-resolution screens for sequence variation in protein-coding regions in a large population unselected for an extreme monogenic clinical phenotype. The consortium reported the detection of a low-frequency missensecoding variant in HNF1A (c.1522G>A (p.E508K)) after sequencing whole exomes of Mexican and US Latino T2D cases (n = 1794) and diabetes-free controls (n = 1962) [78]. This variant was observed in 2.1% of cases and 0.36% non-diabetic controls (OR 5.48; 95% CI 2.83-10.61; p = 4.4 x 10 -7 ); it was significantly associated with a 5-fold increase in T2D prevalence for carriers, and a frequency of 1% in the population [78].…”

“…The consortium reported the detection of a low-frequency missensecoding variant in HNF1A (c.1522G>A (p.E508K)) after sequencing whole exomes of Mexican and US Latino T2D cases (n = 1794) and diabetes-free controls (n = 1962) [78]. This variant was observed in 2.1% of cases and 0.36% non-diabetic controls (OR 5.48; 95% CI 2.83-10.61; p = 4.4 x 10 -7 ); it was significantly associated with a 5-fold increase in T2D prevalence for carriers, and a frequency of 1% in the population [78]. The association of the p.E508K variant in HNF1A with a T2D phenotype was replicated in the T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) Latino group and in a de novo genotyping data set from selfidentified indigenous Mexicans (DMS2) (OR 4.16; 95% CI 2.93-8.38).…”