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

Summary, in English

Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, 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. We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha 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 (=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). This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, 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: Johan Holmkvist; C Cervin; Valeriya Lyssenko; W Winckler; Dragi Anevski; Corrado Cilio; Peter Almgren; Göran Berglund; P Nilsson; Tiinamaija Tuomi; C Lindgren; D Altshuler; Leif Groop
• Avdelning/ar: Translationell Muskel Forskning; Matematisk statistik; Diabetes - immunovirologi; Internmedicin - epidemiologi
• Publiceringsår: 2006
• Språk: Engelska
• Sidor: 2882-2891
• Publikation/Tidskrift/Serie: Diabetologia
• Volym: 49
• Issue: Oct 11
• Länkar: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17033837&dopt=Abstract; http://dx.doi.org/10.1007/s00125-006-0450-x
• Dokumenttyp: Artikel i tidskrift
• Förlag: Springer
• Ämne: Endocrinology and Diabetes
• Nyckelord: insulin; MODY3; prospective studies; type 2 diabetes; mellitus; factor 1-alpha; case-control studies; association study; glucose; hepatocyte nuclear
• Status: Published
• Forskningsgrupp: Genomics, Diabetes and Endocrinology; Diabetes - Immunovirology; Internal Medicine - Epidemiology
• ISBN/ISSN/Övrigt: ISSN: 1432-0428