Genomewide Search for Type 2 Diabetes–Susceptibility Genes in French Whites: Evidence for a Novel Susceptibility Locus for Early-Onset Diabetes on Chromosome 3q27-qter and Independent Replication of a Type 2–Diabetes Locus on Chromosome 1q21–q24

Vionnet, Nathalie; Hani, El Habib; Dupont, Sophie; Gallina, Sophie; Francke, Stephan; Dotte, Sébastien; Matos, Frédérique De; Durand, Emmanuelle; Leprêtre, Frédéric; Lecœur, Cécile; Gallina, P.; Zekiri, Lirije; Dina, Christian; Froguel, Philippe

doi:10.1086/316887

Cited by 622 publications

(458 citation statements)

References 46 publications

Supporting

Mentioning

428

Contrasting

Unclassified

Order By: Relevance

“…In our previous linkage studies based on two selections of French diabetic families, we found moderate significance of linkage to diabetes with a locus near ADA-HNF4α on chromosome 20q13 (MLS=1.72 and 1.81) [1,12]. The highest peak near the marker D20S213 lies 3.5 Mb apart from the genomic location of the HNF4α gene (from UCSC Genome Browser, July 2003).…”

Section: Resultsmentioning

confidence: 78%

See 1 more Smart Citation

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: The gene encoding HNF-4α, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4α P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. Methods: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a casecontrol study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4α region had been shown. Results: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4α was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. Conclusions/interpretation: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4α and type 2 diabetes in several ethnic groups.

show abstract

Section: Resultsmentioning

confidence: 78%

“…The type 2 diabetes French families have been described by Vionnet et al [12]. Informed written consent was obtained from all subjects before participation.…”

Section: Subjectsmentioning

confidence: 99%

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

et al. 2005

View full text Add to dashboard Cite

show abstract

“…This region encodes adiponectin, a 30 kDa protein secreted exclusively by white adipose tissue (WAT), which is capable of increasing insulin sensitivity, stimulating fatty acid oxidation and inhibiting the vascular inflammatory process. 13,14 Skeletal muscle plays an important role in the clearance of blood-free fatty acids and triglyceride, and in whole-body fatty acid oxidation, and CPT is the rate-limiting step for fatty acid oxidation and ketogenesis. 15 Dysregulation of these cytokines can accelerate the process of fat accumulation and glucose intolerance.…”

Section: Introductionmentioning

confidence: 99%

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

et al. 2007

View full text Add to dashboard Cite

Objective: Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short-and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators. Methods: Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured. Results: Caloric intake of the palatable HFD group was 2-3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks. Conclusion: Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD.

show abstract

“…Regions of linkage in several reports overlap with those observed in this HyperGEN analysis. On chromosome 19, linkage was detected at 18 cM for fasting insulin in Pima Indians (LOD 1.33) [23], and for type 2 diabetes and glucose intolerance in young-onset French families at 36 cM (LOD 1.26) [24]. Linkage with fasting glucose, and combined fasting and non-fasting glucose, was detected on chromosome 5 at 0 cM in the Framingham Offspring Study (LOD 1.09) [6], and Framingham Heart Study (LOD 1.65) [25].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: The heritability of fasting serum insulin and glucose concentrations in non-diabetic members of multiplex hypertensive families is unknown. Methods: We calculated the familial aggregation of fasting serum glucose and insulin concentrations and performed a genome-wide scan to assess whether quantitative trait loci contribute to these phenotypes in 2,412 non-diabetic individuals from 1,030 families enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) in the Family Blood Pressure Program. Results: The heritability (±SE) of fasting serum insulin was 0.47±0.085 in European Americans and 0.28±0.08 in African Americans (p<0.0001 for both), after adjusting for age, sex, and BMI. A genomewide scan for fasting serum insulin yielded a maximum log of the odds (LOD) score of 2.36 on chromosome 5 at 20 cM (p=0.0004) in European Americans, and an LOD score of 2.28 on chromosome 19 at 11 cM (p=0.0004) in African Americans. The heritability of fasting serum glucose was 0.5109±0.08 in the former and 0.29±0.09 in the latter (p<0.0003 for both) after adjusting for age, sex and BMI. A genome-wide scan for fasting serum glucose revealed a maximum LOD score of 2.07 on chromosome 5 at 26 cM (p=0.0009) in European Americans. Conclusions/ interpretation: These analyses demonstrate the marked heritability of fasting serum insulin and glucose concentrations in families enriched for the presence of members with hypertension. They suggest that genes associated with fasting serum insulin concentration are present on chromosomes 19 and 5, and that genes associated with fasting serum glucose concentration are on chromosome 5, in families enriched for hypertension.

show abstract

Genomewide Search for Type 2 Diabetes–Susceptibility Genes in French Whites: Evidence for a Novel Susceptibility Locus for Early-Onset Diabetes on Chromosome 3q27-qter and Independent Replication of a Type 2–Diabetes Locus on Chromosome 1q21–q24

Cited by 622 publications

References 46 publications

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

Contact Info

Product

Resources

About