RGD Reference Report - Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes. - Rat Genome Database

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Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes.

Authors: Holmkvist, J  Almgren, P  Lyssenko, V  Lindgren, CM  Eriksson, KF  Isomaa, B  Tuomi, T  Nilsson, P  Groop, L 
Citation: Holmkvist J, etal., Diabetes. 2008 Jun;57(6):1738-44. Epub 2008 Mar 10.
RGD ID: 2301863
Pubmed: PMID:18332101   (View Abstract at PubMed)
DOI: DOI:10.2337/db06-1464   (Journal Full-text)

OBJECTIVE: Mutations in the hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, glucokinase (GCK), and HNF-1beta genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict future type 2 diabetes. RESEARCH DESIGN AND METHODS: We tested 14 previously associated polymorphisms in HNF-1alpha, HNF-4alpha, GCK, and HNF-1beta for association with type 2 diabetes-related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia study (Finland) and in 15,538 individuals from the Malmo Preventive Project (Sweden) with a total follow-up >360,000 years. RESULTS: The polymorphism rs1169288 in HNF-1alpha strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4alpha nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0-1.6], P = 0.03; and 1.1 [1.0-1.2], P = 0.04). The rs2144908 polymorphism in HNF-4alpha was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp (P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up period (P = 0.4; SE 0.004 [-0.003-0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8-1.0], P = 0.1). Polymorphisms in HNF-1beta (transcription factor 2 [TCF2]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes. CONCLUSIONS: In conclusion, genetic variation in both HNF-1alpha and HNF-4alpha predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HNF1AHumantype 2 diabetes mellitus susceptibilityIAGP DNA:SNP::rs1169288 associated with future risk of developing T2DM (p=0.0002) in individuals from the Botnia study in Finland and the Malmo project in SwedenRGD 
HNF4AHumantype 2 diabetes mellitus susceptibilityIAGP DNA:SNP::rs4810424 and rs3212198 nominally associated with future risk of developing T2DM (p=0.04) in individuals from the Botnia study in Finland and the Malmo project in SwedenRGD 
Hnf1aRattype 2 diabetes mellitus susceptibilityISOHNF1A (Homo sapiens)DNA:SNP::rs1169288 associated with future risk of developing T2DM (p=0.0002) (human)RGD 
Hnf1aMousetype 2 diabetes mellitus susceptibilityISOHNF1A (Homo sapiens)DNA:SNP::rs1169288 associated with future risk of developing T2DM (p=0.0002) (human)RGD 
Hnf4aRattype 2 diabetes mellitus susceptibilityISOHNF4A (Homo sapiens)DNA:SNP::rs4810424 and rs3212198 nominally associated with future risk of developing T2DM (p=0.04) (human)RGD 
Hnf4aMousetype 2 diabetes mellitus susceptibilityISOHNF4A (Homo sapiens)DNA:SNP::rs4810424 and rs3212198 nominally associated with future risk of developing T2DM (p=0.04) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GCKHumanHyperglycemia  IAGP DNA:SNPs::rs1799884 , rs2244164 and rs1303722 (human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Hnf1a  (HNF1 homeobox A)
Hnf4a  (hepatocyte nuclear factor 4, alpha)

Genes (Mus musculus)
Hnf1a  (HNF1 homeobox A)
Hnf4a  (hepatic nuclear factor 4, alpha)

Genes (Homo sapiens)
GCK  (glucokinase)
HNF1A  (HNF1 homeobox A)
HNF4A  (hepatocyte nuclear factor 4 alpha)


Additional Information