The Functional Thr130Ile and Val255Met Polymorphisms of the Hepatocyte Nuclear Factor-4α (HNF4A): Gene Associations with Type 2 Diabetes or Altered β-Cell Function among Danes

Ek, Jakob; Rose, Christian Schack; Jensen, D. P.; Glümer, Charlotte; Borch‐Johnsen, Knut; Jørgensen, Torben; Pedersen, Oluf; Hansen, Torben

doi:10.1210/jc.2004-2159

Cited by 35 publications

(35 citation statements)

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“…In a case-control study with a power of Ͼ80% to detect a relative risk of Ͻ1.2 with the observed allele frequency of 12%, we did not find an association with type 2 diabetes. Also, haplotype studies, including previously examined variants in the genomic region (15,18), did not reveal an association with type 2 diabetes. Genotype-quantitative trait studies in 4,456 subjects with NGT and normoglycemia suggested an association between the polymorphism and a reduced fasting level of serum total cholesterol and serum HDL cholesterol, indicating that these linked polymorphisms may affect the expression of HNF4A in the liver.…”

Section: Discussionmentioning

confidence: 82%

“…Among 4,456 subjects with NGT and normoglycemia, there was a significant association between the polymorphism and alterations in fasting levels of serum total cholesterol and HDL cholesterol (P ϭ 0.02 and 0.02, respectively) ( Table 2). Association studies were also carried out using haplotypes based on single nucleotide polymorphisms identified and investigated in previous studies (15,18). However, there were no extended significant associations with diabetes or any relevant pre-diabetic trait for any combinations, including combinations of the Ϫ858c/t polymorphism and the two previously reported diabetes-associated polymorphisms (rs1884614 and Thr130Ile) (data not shown) (15,18).…”

Section: Resultsmentioning

confidence: 92%

“…This finding may indicate that the expression of HNF4A in the liver is also decreased. Interestingly, a missense Thr130Ile HNF4A polymorphism has been described to be associated with decreased circulating total cholesterol levels (18). In contrast to what is typically seen with the majority of MODY1 mutations, the Ϫ192c/g mutation does not seem to be highly penetrant.…”

Section: Discussionmentioning

confidence: 99%

“…For the case-control study, 1,430 type 2 diabetic patients were recruited from the outpatient clinic at Steno Diabetes Center (n ϭ 1,064 patients, including the 114 type 2 diabetic subjects included in the mutation screening) and the population-based Inter99 study, which was performed at the Research Centre for Prevention and Health (Glostrup, Denmark) (n ϭ 366 patients). Control subjects comprised 4,812 individuals with normal glucose tolerance (NGT) and normoglycemia who were recruited from the populationbased Inter99 study (n ϭ 4,456) and randomly selected subjects from the Danish Central Population Register (n ϭ 356) (18,19). The studies were approved by the local ethical committees of Copenhagen and Charles University (Prague) and were carried out in accordance with the principles of the Declaration of Helsinki II.…”

Section: Methodsmentioning

confidence: 99%

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A Novel −192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-Onset Diabetes

Hansen

Lajer

et al. 2006

Diabetes

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Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4␣ gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A ؊192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the ؊192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P ‫؍‬ 0.004). Examination of the families showed that carriers of the ؊192c/g mutation had a significantly impaired glucosestimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions ؊1107g/t and ؊858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.

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Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

A Novel −192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-Onset Diabetes

Hansen

Lajer

et al. 2006

Diabetes

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show abstract

“…17,25,26 HNF4a is expressed in different tissues, and mutated proteins may have wide ranging effects. The HNF4a gene is highly conserved across species, with two activation function domains, AF-1 and AF-2, a DNA-binding domain and a putative ligand-binding domain.…”

Section: Discussionmentioning

confidence: 99%

PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

et al. 2007

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Genetic polymorphism of hepatocyte nuclear factor‐4α influences human cytochrome P450 2D6 activity†

et al. 2008

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Hepatocyte nuclear factor-4 alpha (HNF4A) is an essential transcriptional regulator for many genes that are expressed preferentially in the liver. Among the important functions of the liver is drug metabolism in response to xenobiotic exposure. Recent studies have suggested that HNF4A regulates the expression of cytochrome P450 (CYP), including CYP2D6 and CYP3A4, which show large individual variations in their activities. To understand the genetic factors that influence individual CYP activities, a genetic variant of HNF4A and the effects of genetic variants of HNF4A on CYP activity were investigated. Here, we report the identification of a novel coding variant of HNF4A that influences CYP2D6 activity in humans. After direct sequencing, a polymorphism search revealed the HNF4A G60D variant in Koreans. This variant was unable to bind to the recognition site in the CYP2D6 promoter and therefore lacked the regulatory function for this gene. Human liver specimens with the heterozygous HNF4A G60D genotype showed a tendency toward lower levels of CYP2D6 activity than the wild-type genotype in the same genetic background of CYP2D6. Furthermore, human subjects with the HNF4A G60D genotype tended to have lower CYP2D6 activity than those with the wild-type HNF4A. The HNF4A G60D variant was detected at low frequency in Asian populations, including Koreans, Chinese, and Vietnamese, and was not found in Africans or Caucasians. Conclusion: This is the first report to show that the genetic polymorphism of liver-enriched nuclear receptor HNF4A influences downstream CYP2D6 function in human subjects. (HEPATOLOGY 2008;48:635-645.) T he nuclear receptor hepatocyte nuclear factor 4 alpha (HNF4A; also called NR2A1) is a transcriptional regulator of genes in the transport and metabolism of glucose and lipids. Through a complex hierarchical transcriptional network, HNF4A plays an essential role in the normal physiologic functions of hepatocytes and pancreatic cells. 1 In the pancreas, HNF4A regulates the expression of genes that are involved in glucose metabolism and insulin secretion. 2 The important role of HNF4A in glucose homeostasis is exemplified by the identification of HNF4A mutants in certain types of diabetes. Maturity onset of diabetes in the young, which is a rare form of non-insulin-dependent diabetes mellitus, is a dominantly inherited disease that is characterized by defective glucose-dependent secretion of insulin by pancreatic ␤-cells. Nonsense, missense, and frameshift mutations in the human HNF4A gene have been identified in maturity onset of diabetes in the young patients. Those mutations include R154Stop, Q268Stop, F75delT, K99fsdelAA, G115S, R127W, V255M, E276Q, and V393I (reviewed by Ryffel 3 ). Because HNF4A is also expressed in other tissues,

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The Functional Thr130Ile and Val255Met Polymorphisms of the Hepatocyte Nuclear Factor-4α (HNF4A): Gene Associations with Type 2 Diabetes or Altered β-Cell Function among Danes

Cited by 35 publications

References 55 publications

A Novel −192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-Onset Diabetes

A Novel −192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-Onset Diabetes

PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

Genetic polymorphism of hepatocyte nuclear factor‐4α influences human cytochrome P450 2D6 activity†

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