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


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
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.
Holmkvist
J
J
Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Center, Malmö University Hospital, Lund University, S-205 02, Malmö, Sweden.
Cervin
C
C
Lyssenko
V
V
Winckler
W
W
Anevski
D
D
Cilio
C
C
Almgren
P
P
Berglund
G
G
Nilsson
P
P
Tuomi
T
T
Lindgren
C M
CM
Altshuler
D
D
Groop
L
L
D000328:Adult; D019943:Amino Acid Substitution; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005947:Glucose / Q000494:pharmacology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D050177:Overweight; D010957:Plasmids; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014158:Transcription, Genetic
D001786:Blood Glucose; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D001120:Arginine; D005947:Glucose