Association of a Low-frequency Variant in HNF1A with Type 2 Diabetes in a Latino Population

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.

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References

Baumhueter S, Mendel D, Conley P, Kuo C, Turk C, Graves M . HNF-1 shares three sequence motifs with the POU domain proteins and is identical to LF-B1 and APF. Genes Dev. 1990; 4(3):372-9. DOI: 10.1101/gad.4.3.372. View

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

Bjorkhaug L, Ye H, Horikawa Y, Sovik O, Molven A, Njolstad P . MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X). Biochem Biophys Res Commun. 2001; 279(3):792-8. DOI: 10.1006/bbrc.2000.4024. View

Chouard T, BLUMENFELD M, Bach I, Vandekerckhove J, Cereghini S, Yaniv M . A distal dimerization domain is essential for DNA-binding by the atypical HNF1 homeodomain. Nucleic Acids Res. 1990; 18(19):5853-63. PMC: 332325. DOI: 10.1093/nar/18.19.5853. View

FALCONER D . The inheritance of liability to diseases with variable age of onset, with particular reference to diabetes mellitus. Ann Hum Genet. 1967; 31(1):1-20. DOI: 10.1111/j.1469-1809.1967.tb01249.x. View

Bellanne-Chantelot C, Carette C, Riveline J, Valero R, Gautier J, Larger E . The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes. 2007; 57(2):503-8. DOI: 10.2337/db07-0859. View

Molven A, Njolstad P . Role of molecular genetics in transforming diagnosis of diabetes mellitus. Expert Rev Mol Diagn. 2011; 11(3):313-20. DOI: 10.1586/erm.10.123. View

Shields B, Hicks S, Shepherd M, Colclough K, Hattersley A, Ellard S . Maturity-onset diabetes of the young (MODY): how many cases are we missing?. Diabetologia. 2010; 53(12):2504-8. DOI: 10.1007/s00125-010-1799-4. View

Kropff J, Selwood M, McCarthy M, Farmer A, Owen K . Prevalence of monogenic diabetes in young adults: a community-based, cross-sectional study in Oxfordshire, UK. Diabetologia. 2011; 54(5):1261-3. DOI: 10.1007/s00125-011-2090-z. View

10.

Tennessen J, Bigham A, OConnor T, Fu W, Kenny E, Gravel S . Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012; 337(6090):64-9. PMC: 3708544. DOI: 10.1126/science.1219240. View

11.

Barquera S, Tovar-Guzman V, Campos-Nonato I, Gonzalez-Villalpando C, Rivera-Dommarco J . Geography of diabetes mellitus mortality in Mexico: an epidemiologic transition analysis. Arch Med Res. 2003; 34(5):407-14. DOI: 10.1016/S0188-4409(03)00075-4. View

12.

Hanis C, Ferrell R, Barton S, Aguilar L, Tulloch B, Garcia C . Diabetes among Mexican Americans in Starr County, Texas. Am J Epidemiol. 1983; 118(5):659-72. DOI: 10.1093/oxfordjournals.aje.a113677. View

13.

Li B, Leal S . Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet. 2008; 83(3):311-21. PMC: 2842185. DOI: 10.1016/j.ajhg.2008.06.024. View

14.

Villalpando S, Cruz V, Rojas R, Shamah-Levy T, Avila M, Gaona B . Prevalence and distribution of type 2 diabetes mellitus in Mexican adult population: a probabilistic survey. Salud Publica Mex. 2010; 52 Suppl 1:S19-26. DOI: 10.1590/s0036-36342010000700005. View

15.

Winckler W, Weedon M, Graham R, McCarroll S, Purcell S, Almgren P . Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes. Diabetes. 2007; 56(3):685-93. DOI: 10.2337/db06-0202. View

16.

Morris A, Voight B, Teslovich T, Ferreira T, V Segre A, Steinthorsdottir V . Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012; 44(9):981-90. PMC: 3442244. DOI: 10.1038/ng.2383. View

17.

Ellard S . Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum Mutat. 2000; 16(5):377-85. DOI: 10.1002/1098-1004(200011)16:5<377::AID-HUMU1>3.0.CO;2-2. View

18.

Pearson E, Starkey B, Powell R, Gribble F, Clark P, Hattersley A . Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet. 2003; 362(9392):1275-81. DOI: 10.1016/S0140-6736(03)14571-0. View

19.

Zuk O, Schaffner S, Samocha K, Do R, Hechter E, Kathiresan S . Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci U S A. 2014; 111(4):E455-64. PMC: 3910587. DOI: 10.1073/pnas.1322563111. View

20.

Tronche F, Yaniv M . HNF1, a homeoprotein member of the hepatic transcription regulatory network. Bioessays. 1992; 14(9):579-87. DOI: 10.1002/bies.950140902. View