Is a rare HNF1A gene variant associated with higher odds of type 2 diabetes in Latino populations?

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Latino populations have one of the highest prevalences of type 2 diabetes worldwide. This study investigated associations between rare protein-coding genetic variants and type 2 diabetes prevalence in a large Latino population, while exploring potential molecular and physiological mechanisms behind those relationships.

The genetic association study used whole-exome sequencing of DNA samples from 3756 Mexican and US Latino individuals recruited from 1993 to 2013: 1794 with type 2 diabetes and 1962 without diabetes. One variant was then tested for allele frequency and association with type 2 diabetes in large multiethnic data sets comprising 14,276 participants and was characterized in experimental assays. The primary outcome was type 2 diabetes prevalence. Secondary outcomes included age at onset, body mass index (BMI), and effects on protein function.

A single rare missense variant, c.1522G>A [p.E508K], in hepatocyte nuclear factor 1-α (HNF1A) was associated with type 2 diabetes prevalence: odds ratio (OR), 5.48; 95% confidence interval (CI), 2.83–10.61; P = 4.4 × 10⁻⁷. HNF1A is the gene responsible for maturity-onset diabetes of the young type 3 (MODY3). The variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of those with it.

In the multiethnic replication data sets, p.E508K was observed only in Latino participants, whose group included 1443 people with type 2 diabetes and 1673 without it. It was associated with type 2 diabetes in that group (OR, 4.16; 95% CI, 1.75–9.92; P = .0013). In experimental assays, the HNF-1A protein carrying p.E508K showed reduced transactivation activity at its target promoter compared with the wild-type protein.

Among participants with type 2 diabetes, carriers and noncarriers of p.E508K did not differ significantly in the clinical characteristics compared, including age at onset. Mean age (SD) was 45.3 years (11.2) for carriers versus 47.5 years (11.5) for noncarriers (P = .49); mean BMI (SD) was 28.2 (5.5) versus 29.3 (5.3), respectively (P = .19).

The researchers concluded that whole-exome sequencing 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. The finding may have implications for screening and treatment modification in this population, but additional studies are required.