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

JAMA
Authors
Keywords
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.

Year of Publication
2014
Journal
JAMA
Volume
311
Issue
22
Pages
2305-14
Date Published
2014 Jun 11
ISSN
1538-3598
URL
DOI
10.1001/jama.2014.6511
PubMed ID
24915262
PubMed Central ID
PMC4425850
Links
Grant list
U01 DK085501 / DK / NIDDK NIH HHS / United States
U01DK085501 / DK / NIDDK NIH HHS / United States
UM1 CA164973 / CA / NCI NIH HHS / United States
R01 CA80205 / CA / NCI NIH HHS / United States
U01 DK057295 / DK / NIDDK NIH HHS / United States
R35CA53890 / CA / NCI NIH HHS / United States
R01 DK098032 / DK / NIDDK NIH HHS / United States
U01DK085526 / DK / NIDDK NIH HHS / United States
R01DK053889 / DK / NIDDK NIH HHS / United States
R01 DK057295 / DK / NIDDK NIH HHS / United States
R01 CA144034 / CA / NCI NIH HHS / United States
R01 DK047482 / DK / NIDDK NIH HHS / United States
R01 DK033665 / DK / NIDDK NIH HHS / United States
CA164973 / CA / NCI NIH HHS / United States
R01 DK042273 / DK / NIDDK NIH HHS / United States
R35 CA053890 / CA / NCI NIH HHS / United States
R01 CA055069 / CA / NCI NIH HHS / United States
CA063464 / CA / NCI NIH HHS / United States
CA054281 / CA / NCI NIH HHS / United States
R01 CA063464 / CA / NCI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
P01 HL045522 / HL / NHLBI NIH HHS / United States
R01DK047482 / DK / NIDDK NIH HHS / United States
R01 CA054281 / CA / NCI NIH HHS / United States
U01 CA063464 / CA / NCI NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 CA080205 / CA / NCI NIH HHS / United States
R01HL24799 / HL / NHLBI NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
P01HL045522 / HL / NHLBI NIH HHS / United States
U01 CA164973 / CA / NCI NIH HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
R01 DK053889 / DK / NIDDK NIH HHS / United States