Variants in the hepatocyte nuclear factor-1alpha and -4alpha genes in Finnish and Chinese subjects with late-onset type 2 diabetes.
OBJECTIVE
To determine the role of the hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha genes in the etiology of late-onset type 2 diabetes in Finnish and Chinese subjects.


METHODS
The whole coding regions of the genes encoding for HNF-1alpha and HNF-4alpha, including approximately 800 bp of the HNF-1alpha promoter, were investigated in 40 Finnish subjects (fasting C-peptide 50-570 pmol/l) and 47 Chinese subjects with type 2 diabetes by single-strand conformation polymorphism (SSCP) analysis. Frequencies of the variants of these genes were analyzed by restriction fragment-length polymorphism analysis in additional samples of 100 Finnish diabetic patients and 82 Finnish control subjects and in 58 Chinese diabetic patients and 51 Chinese control subjects.


RESULTS
No previously reported gene defects were detected, but one novel functionally silent GCC-->GCG variant (nucleotide 73, exon 10) was observed in the HNF-4alpha gene in a Chinese diabetic patient. Interestingly, the Ala98Val substitution of the HNF-1alpha gene occurred at a significantly higher frequency in 140 Finnish diabetic patients compared with 82 control subjects (P = 0.014). The Ala98Val variant was not, however, associated with abnormalities in insulin secretion evaluated by oral and intravenous glucose tolerance tests in subjects with normal (n = 295) or impaired (n = 38) glucose tolerance.


CONCLUSIONS
Variants in the HNF-1alpha and HNF-4alpha genes are unlikely to play a major role in the pathogenesis of late-onset type 2 diabetes in Finnish and Chinese subjects. However, the association of the Ala98Val variant of the HNF-1alpha gene with type 2 diabetes in Finnish subjects may indicate a diabetogenic locus close to the HNF-1alpha gene.
Rissanen
J
J
Department of Medicine, University of Kuopio, Finland.
Wang
H
H
Miettinen
R
R
Kärkkäinen
P
P
Kekäläinen
P
P
Mykkänen
L
L
Kuusisto
J
J
Karhapää
P
P
Niskanen
L
L
Uusitupa
M
M
Laakso
M
M
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000409:Alanine; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002096:C-Peptide / Q000097:blood; D002681:China; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005260:Female; D005387:Finland; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014633:Valine; D044465:White People / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002096:C-Peptide; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D014633:Valine; D000409:Alanine