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Sökning: WFRF:(Karpe Fredrik)

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  • Speliotes, Elizabeth K., et al. (författare)
  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
  • 2010
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 42:11, s. 53-937
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
  • Amisten, Stefan, et al. (författare)
  • An atlas of G-protein coupled receptor expression and function in human subcutaneous adipose tissue.
  • 2015
  • Ingår i: Pharmacology and Therapeutics. - : Elsevier. - 0163-7258. ; 146:Sep 19, s. 61-93
  • Forskningsöversikt (refereegranskat)abstract
    • G-protein coupled receptors (GPCRs) are involved in the regulation of adipose tissue function, but the total number of GPCRs expressed by human subcutaneous adipose tissue, as well as their function and interactions with drugs, is poorly understood. We have constructed an atlas of all GPCRs expressed by human subcutaneous adipose tissue: the 'adipose tissue GPCRome', to support the exploration of novel control nodes in metabolic and endocrine functions. This atlas describes how adipose tissue GPCRs regulate lipolysis, insulin resistance and adiponectin and leptin secretion. We also discuss how adipose tissue GPCRs interact with their endogenous ligands and with GPCR-targeting drugs, with a focus on how drug/receptor interactions may affect lipolysis, and present a model predicting how GPCRs with unknown effects on lipolysis might modulate cAMP-regulated lipolysis. Subcutaneous adipose tissue expresses 163 GPCRs, a majority of which have unknown effects on lipolysis, insulin resistance and adiponectin and leptin secretion. These GPCRs are activated by 180 different endogenous ligands, and are the targets of a large number of clinically used drugs. We identified 119 drugs, acting on 23 GPCRs, that are predicted to stimulate lipolysis and 173 drugs, acting on 25 GPCRs, that are predicted to inhibit lipolysis. This atlas highlights knowledge gaps in the current understanding of adipose tissue GPCR function, and identifies GPCR/ligand/drug interactions that might affect lipolysis, which is important for understanding and predicting metabolic side effects of drugs. This approach may aid in the design of new, safer therapeutic agents, with fewer undesired effects on lipid homeostasis.
  • Andersson, Jonas, et al. (författare)
  • Association of adipose tissue blood flow with fat depot sizes and adipokines in women
  • 2012
  • Ingår i: International Journal of Obesity. - : Nature Publishing Group. - 0307-0565 .- 1476-5497. ; 36:6, s. 783-789
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To explore possible associations between adipose tissue (AT) blood flow (ATBF), AT depot sizes and adipocyte-derived hormones (adipokines) in women.Subjects: In all, 43 healthy women were divided into four groups: normal-weight (n=11) and obese (n=11) pre-menopausal women and normal-weight (n=10) and obese (n=11) post-menopausal women.Methods: Fasting levels of adipokines were obtained, and a single-slice computed tomography scan at the level of L4-L5 was used to estimate fat depot sizes. ATBF was assessed by xenon washout while in a fasting state and after oral glucose load. We also measured glucose, insulin and non-esterified fatty acids.Results: Total, subcutaneous and visceral AT areas strongly correlated with ATBF (all P<0.001). Circulating leptin levels strongly and inversely correlated with ATBF (P=0.001), but this association did not remain after adjustment for body mass index. Adiponectin was not associated with blood flow.Conclusion: ATBF is closely linked to subcutaneous and visceral AT size. Further analyses are needed to determine possible mediators of this association, including mechanistic studies to assess a putative role for leptin as a significant modulator of blood flow. International Journal of Obesity advance online publication, 26 July 2011; doi:10.1038/ijo.2011.152.
  • Andersson, Jonas, et al. (författare)
  • Dysregulation of subcutaneous adipose tissue blood flow in overweight postmenopausal women
  • 2010
  • Ingår i: Menopause. - 1072-3714 .- 1530-0374. ; 17:2, s. 365-371
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: A putative link between abdominal obesity and metabolic-vascular complications after menopause may be due to a decreased adipose tissue blood flow (ATBF). The present work aimed to analyze possible changes in ATBF with being overweight and menopausal and its putative link to endothelial dysfunction and autonomic nervous system balance.METHODS: Forty-three healthy women were classified into four groups according to weight and menopause status. The ATBF was measured by xenon washout while fasting and after oral glucose intake. The nitric oxide synthase inhibitor asymmetric dimethylarginine was used as a marker of endothelial function and heart rate variability-estimated autonomic nervous system activity.RESULTS: Fasting ATBF was decreased in both overweight groups (P = 0.044 and P = 0.048) versus normal-weight premenopausal women. Normal-weight and overweight postmenopausal women exhibited lower maximum ATBF compared with normal-weight premenopausal women (P = 0.015 and P = 0.001, respectively), and overweight postmenopausal women exhibited lower maximum ATBF compared with normal-weight postmenopausal women (P = 0.003). A negative correlation was found between fasting ATBF and asymmetric dimethylarginine (P = 0.015), whereas maximum ATBF was negatively associated with sympathetic-parasympathetic nervous system balance (ratio of the power of the low frequency to the power of the high frequency; P = 0.002).CONCLUSIONS: Loss of ATBF flexibility in overweight postmenopausal women may contribute to the metabolic dysfunction seen in this group of women.
  • Berndt, Sonja I., et al. (författare)
  • Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
  • 2013
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 45:5, s. 501-512
  • Tidskriftsartikel (refereegranskat)abstract
    • Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
  • Corbin, Laura J., et al. (författare)
  • Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference
  • 2018
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.
  • Drong, Alexander W, et al. (författare)
  • The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue.
  • 2013
  • Ingår i: PLOS ONE. - 1932-6203. ; 8:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.
  • Dupuis, Josee, et al. (författare)
  • New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
  • 2010
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 42:2, s. 32-105
  • Tidskriftsartikel (refereegranskat)abstract
    • Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
  • Erzurumluoglu, A. Mesut, et al. (författare)
  • Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
  • 2020
  • Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
  • Tidskriftsartikel (refereegranskat)abstract
    • Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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