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Sökning: swepub > (2000-2011) > Groop Leif > Ridderstråle Martin

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1.
  • Heid, Iris M., et al. (författare)
  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:11, s. 949
  • Tidskriftsartikel (refereegranskat)abstract
    • Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 x 10(-9) to P = 1.8 x 10(-40)) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 x 10(-3) to P = 1.2 x 10(-13)). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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2.
  • Lango Allen, Hana, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - 1476-4687. ; 467:7317, s. 832
  • Tidskriftsartikel (refereegranskat)abstract
    • Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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4.
  • Ahlzén, Maja, et al. (författare)
  • Expression of the transcription factor 7-like 2 gene (TCF7L2) in human adipocytes is down regulated by insulin.
  • 2008
  • Ingår i: Biochemical and biophysical research communications. - 1090-2104. ; 370, s. 49-52
  • Tidskriftsartikel (refereegranskat)abstract
    • Variants in the TCF7L2 gene (transcription factor 7-like 2) have shown strong association with type 2 diabetes with two defined risk haplotypes, HapA and HapB(T2D). TCF7L2 may play a role in both glucose homeostasis and adipogenesis. Our aim was to characterize the TCF7L2 mRNA expression and regulation in human adipose tissue. We quantified TCF7L2 mRNA levels in cultured human adipocytes and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissue from 38 obese non-diabetic subjects, using real-time PCR. The influence of haplotype and clinical traits on TCF7L2 mRNA levels were investigated. In vitro, insulin decreased TCF7L2 mRNA expression. This effect was attenuated in cells incubated with the free fatty acids palmitate or oleate. In vivo, we found significantly higher expression in SAT from more insulin resistant subjects. No correlations between TCF7L2 mRNA expression and obesity measures were observed. TCF7L2 expression was higher in VAT than in SAT and when stratifying for haplotype, this difference was seen in HapA carriers but not in non-HapA carriers. In conclusion, TCF7L2 mRNA levels in adipocytes are decreased by insulin and seem to increase in insulin resistant subjects and in HapA carriers.
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5.
  • Carlsson, Emma, et al. (författare)
  • Genetic and Nongenetic Regulation of CAPN10 mRNA Expression in Skeletal Muscle.
  • 2005
  • Ingår i: Diabetes. - American Diabetes Association. - 0012-1797. ; 54:10, s. 3015-3020
  • Tidskriftsartikel (refereegranskat)abstract
    • The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes–associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.
6.
  • Carlsson, Emma, et al. (författare)
  • Role of the FOXC2 -512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome.
  • 2005
  • Ingår i: Int J Obes Relat Metab Disord. - Nature Publishing Group. - 0307-0565. ; 29:Dec 14, s. 268-274
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Overexpression of the human transcription factor FOXC2 gene ( FOXC2) protects against insulin resistance in mice and a common FOXC2 polymorphism (-512C > T) has been suggested to be associated with insulin resistance in humans. Here, we addressed the potential role for FOXC2 as a candidate gene for type 2 diabetes and associated phenotypes. MATERIALS AND METHODS: A case-control study was performed in 390 type 2 diabetic patients and 307 control subjects. The number of patients was increased to a total of 768 subjects for further study of phenotypic differences relating to the dysmetabolic syndrome relative to genetic variation. The FOXC2 -512C > T polymorphism was genotyped by a restriction fragment length polymorphism PCR assay. RESULTS: FOXC2 -512C > T allele and genotype distribution did not differ between patients with type 2 diabetes and control subjects, but the C/C genotype was associated with increased body mass index (BMI, kg/m(2)) (P-a = 0.03) among type 2 diabetic patients. The FOXC2 -512C > T polymorphism was a significant independent predictor of BMI (P = 0.001) in a multiple regression model including age, gender and affection status. We found no significant association with type 2 diabetes-related metabolic parameters but that the C-allele (P = 0.01) and C/C and C/T genotypes (P = 0.03) were significantly over-represented in type 2 diabetic males with a concomitant diagnosis of dysmetabolic syndrome. CONCLUSION: We conclude that FOXC2 is associated with obesity and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes.
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8.
  • Carlsson, Emma, et al. (författare)
  • The hormone-sensitive lipase C-60G promoter polymorphism is associated with increased waist circumference in normal-weight subjects.
  • 2006
  • Ingår i: Int J Obes (Lond). - Nature Publishing Group. - 0307-0565. ; 30:9, s. 1442-1448
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from triglyceride stores in adipocytes. The aim of the present study was to investigate the role of the HSL gene promoter variant C-60G, a polymorphism which previously has been associated with reduced promoter activity in vitro, in obesity and type 2 diabetes. DESIGN: We genotyped two materials consisting of obese subjects and non-obese controls, one material with offspring-parents trios, where the offspring was abdominally obese and one material with trios, where the offspring had type 2 diabetes or impaired glucose homeostasis. HSL promoter containing the HSL C-60G G-allele was generated and tested against a construct with the C-allele in HeLa cells and primary rat adipocytes. HSL mRNA levels were quantified in subcutaneous and visceral fat from 33 obese subjects. RESULTS: We found that the common C-allele was associated with increased waist circumference and WHR in lean controls, but there was no difference in genotype frequency between obese and non-obese subjects. There was a significant increased transmission of C-alleles to the abdominally obese offspring but no increased transmission of C-alleles was observed to offspring with impaired glucose homeostasis. The G-allele showed reduced transcription in HeLa cells and primary rat adipocytes. HSL mRNA levels were significantly higher in subcutaneous compared to visceral fat from obese subjects. CONCLUSION: The HSL C-60G polymorphism is associated with increased waist circumference in non-obese subjects.
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9.
10.
  • Cervin, Camilla, et al. (författare)
  • Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.
  • 2002
  • Ingår i: Diabetologia. - Springer Berlin / Heidelberg. - 0012-186X. ; 45:12, s. 1703-1708
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene. METHODS: Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. RESULTS: Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.
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