Common variants in HNF-1 α and risk of type 2 diabetes
Artikel i vetenskaplig tidskrift, 2006

Aims/hypothesis: Mutations in the hepatocyte nuclear factor 1-α gene (HNF-1α, 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-1α 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-1α 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/m2) 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-1α, 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.

Författare

J. Holmkvist

Skånes universitetssjukhus (SUS)

C. Cervin

Skånes universitetssjukhus (SUS)

V. Lyssenko

Skånes universitetssjukhus (SUS)

W. Winckler

Broad Institute

Massachusetts General Hospital

Dragi Anevski

Göteborgs universitet

Chalmers, Matematiska vetenskaper

C. Cilio

Skånes universitetssjukhus (SUS)

P. Almgren

Skånes universitetssjukhus (SUS)

G. Berglund

Skånes universitetssjukhus (SUS)

P. Nilsson

Skånes universitetssjukhus (SUS)

T. Tuomi

Folkhalsan

Helsinki University Central Hospital

C. M. Lindgren

NOVUM

Karolinska universitetssjukhuset

D. Altshuler

Broad Institute

Massachusetts General Hospital

L. Groop

Helsinki University Central Hospital

Skånes universitetssjukhus (SUS)

Diabetologia

0012-186X (ISSN) 1432-0428 (eISSN)

Vol. 49 2882-2891

Ämneskategorier

Dermatologi och venereologi

DOI

10.1007/s00125-006-0450-x