| 1. |
- Lindgren, Cecilia M, et al.
(author)
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Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
- 2009
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
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Journal article (peer-reviewed)abstract
- To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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| 2. |
- Newton-Cheh, Christopher, et al.
(author)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Journal article (peer-reviewed)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 3. |
- Kotronen, A., et al.
(author)
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A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans
- 2009
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52:6, s. 1056-1060
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Journal article (peer-reviewed)abstract
- It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity; and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver. We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic-hyperinsulinaemic (insulin infusion 0.3 mU kg(-1) min(-1)) clamp technique combined with infusion of [3-H-3]glucose in 109 participants. The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p = 0.011) and serum aspartate aminotransferase concentrations (p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r = 0.62, p < 0.0001) and to liver fat content (r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m(2)). A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.
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| 4. |
- Kotronen, Anna, et al.
(author)
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Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts
- 2009
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In: European Journal of Endocrinology. - 1479-683X. ; 160:4, s. 593-602
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Journal article (peer-reviewed)abstract
- Aims: We investigated whether polymorph isms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver I, at content. Methods: Liver fat content was measured using proton magnetic resonance spectroscopy (H-1-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4). acliponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were Studied in two independent cohorts and related to surrogate markers of liver fat content. Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with H-1-MRS after adjusting for age, gender, and BMI, Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of similar to 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum gamma glutamyltransfer concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of similar to 3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations. Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.
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| 5. |
- Malmgren, Siri, et al.
(author)
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Tight coupling between glucose and mitochondrial metabolism in clonal beta-cells is required for robust insulin secretion.
- 2009
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In: Journal of Biological Chemistry. - 1083-351X. ; 284, s. 32395-32404
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Journal article (peer-reviewed)abstract
- The biochemical mechanisms underlying glucose-stimulated insulin secretion from pancreatic beta-cells are not completely understood. To identify metabolic disturbances in beta-cells that impair glucose-stimulated insulin secretion, we compared two INS-1-derived clonal beta-cell lines, which are glucose-responsive (832/13) or glucose-unresponsive (832/2). We found that despite a marked impairment of glucose-stimulated insulin secretion, 832/2 cells exhibited a higher rate of glycolysis. Still, no glucose-induced increases in respiratory rate, ATP production or respiratory chain complex I, III and IV activities were seen in the 832/2 cells. Instead, 832/2 cells, which expressed lactate dehydrogenase, released lactate regardless of ambient glucose concentrations. In contrast, the glucose-responsive 832/13 line lacked lactate dehydrogenase and did not produce lactate. Accordingly, in 832/2 cells mRNA expression of genes for glycolytic enzymes were up-regulated, whereas mitochondria-related genes were down-regulated. In human islets, mRNA expression of genes such as lactate dehydrogenase A and hexokinase I correlated positively with long-term glucose homeostasis reflected by HbA1c levels, while that of Slc2a2 (GLUT2) correlated negatively with Hb1Ac. We conclude that tight metabolic regulation enhancing mitochondrial metabolism and restricting glycolysis in 832/13 cells is required for clonal beta-cells to secrete insulin robustly in response to glucose. Moreover, a similar expression pattern of genes controlling glycolytic and mitochondrial metabolism in clonal beta-cells and human islets was observed, suggesting that a similar prioritization of mitochondrial metabolism is required in healthy human beta-cells. The 832 beta-cell lines may be helpful tools to resolve metabolic perturbations occurring in Type 2 Diabetes.
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| 6. |
- Pramfalk, C, et al.
(author)
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Control of ACAT2 Liver Expression by HNF4{alpha}. Lesson From MODY1 Patients.
- 2009
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 29:8, s. 1235-1241
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Journal article (peer-reviewed)abstract
- OBJECTIVE: ACAT2 is thought to be responsible for cholesteryl ester production in chylomicron and VLDL assembly. Recently, we identified HNF1alpha as an important regulator of the human ACAT2 promoter. Thus, we hypothesized that MODY3 (HNF1alpha gene mutations) and possibly MODY1 (HNF4alpha, upstream regulator of HNF1alpha, gene mutations) subjects may have lower VLDL esterified cholesterol. METHODS AND RESULTS: Serum analysis and lipoprotein separation using size-exclusion chromatography were performed in controls and MODY1 and MODY3 subjects. In vitro analyses included mutagenesis and cotransfections in HuH7 cells. Finally, the relevance in vivo of these findings was tested by ChIP assays in human liver. Whereas patients with MODY3 had normal lipoprotein composition, those with MODY1 had lower levels of VLDL and LDL esterified cholesterol, as well as of VLDL triglyceride. Mutagenesis revealed one important HNF4 binding site in the human ACAT2 promoter. ChIP assays and protein-to-protein interaction studies showed that HNF4alpha, directly or indirectly (via HNF1alpha), can bind to the ACAT2 promoter. CONCLUSIONS: We identified HNF4alpha as an important regulator of the hepatocyte-specific expression of the human ACAT2 promoter. Our results suggest that the lower levels of esterified cholesterol in VLDL- and LDL-particles in patients with MODY1 may-at least in part-be attributable to lower ACAT2 activity in these patients.
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