Common variants in HNF-1 alpha and risk of type 2 diabetes.

Abstract

AIMS/HYPOTHESIS:

Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes.

SUBJECTS AND METHODS:

We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo.

RESULTS:

Certain combinations of the I27L and A98V polymorphisms in the HNF-1alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n = 2,293; p = 0.003). In a new case-control (n = 1,511 and n = 2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR) = 1.5 (p = 0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR = 2.3, p = 0.002).

CONCLUSIONS/INTERPRETATION:

This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.

• Authors: J Holmkvist, C Cervin, V Lyssenko, W Winckler, D Anevski, C Cilio, P Almgren, G Berglund, P Nilsson, T Tuomi, C M Lindgren, D Altshuler, L Groop
• Journal: Diabetologia (Diabetologia) Vol. 49 Issue 12 Pg. 2882-91 (Dec 2006) ISSN: 0012-186X [Print] Germany
• PMID: 17033837 (Publication Type: Journal Article, Multicenter Study)

Chemical References

• Blood Glucose
• Hepatocyte Nuclear Factor 1-alpha
• Insulin
• Arginine
• Glucose

Topics

• Adult
• Amino Acid Substitution
• Arginine (pharmacology)
• Blood Glucose (metabolism)
• Body Weight
• Case-Control Studies
• Diabetes Mellitus, Type 2 (epidemiology, genetics)
• Female
• Genetic Variation
• Glucose (pharmacology)
• Hepatocyte Nuclear Factor 1-alpha (genetics)
• Humans
• Insulin (metabolism)
• Insulin Secretion
• Male
• Middle Aged
• Mutagenesis, Site-Directed
• Overweight
• Plasmids
• Polymorphism, Single Nucleotide
• Risk Factors
• Transcription, Genetic