245 results found
van der Harst P, Zhang W, Leach IM, et al., 2012, Seventy-five genetic loci influencing the human red blood cell, NATURE, Vol: 492, Pages: 369-+, ISSN: 0028-0836
Gieger C, Radhakrishnan A, Cvejic A, et al., 2011, New gene functions in megakaryopoiesis and platelet formation, NATURE, Vol: 480, Pages: 201-208, ISSN: 0028-0836
Ehret GB, Munroe PB, Rice KM, et al., 2011, Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk, NATURE, Vol: 478, Pages: 103-109, ISSN: 0028-0836
Teslovich TM, Musunuru K, Smith AV, et al., 2010, Biological, clinical and population relevance of 95 loci for blood lipids, Nature, Vol: 466, Pages: 707-713, ISSN: 0028-0836
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10−8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Chambers JC, Zhang W, Lord GM, et al., 2010, Genetic loci influencing kidney function and chronic kidney disease, NATURE GENETICS, Vol: 42, Pages: 373-375, ISSN: 1061-4036
Chambers JC, Zhao J, Terracciano CMN, et al., 2010, Genetic variation in SCN10A influences cardiac conduction, NATURE GENETICS, Vol: 42, Pages: 149-U80, ISSN: 1061-4036
Zabaneh D, Chambers JC, Elliott P, et al., 2009, Heritability and genetic correlations of insulin resistance and component phenotypes in Asian Indian families using a multivariate analysis, DIABETOLOGIA, Vol: 52, Pages: 2585-2589, ISSN: 0012-186X
Elliot P, Chambers J, Sehmi J, et al., 2009, Does CRP Play a Causal Role in the Development of Coronary Heart Disease: Results of a Mendelian Randomisation Experiment Involving 128,935 People, 82nd Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S467-S468, ISSN: 0009-7322
Chambers J, Zhao J, Terracciano C, et al., 2009, Genetic Variation in SCN10a is Associated With Cardiac Conduction, Heart Block and Risk of Ventricular Fibrillation, 82nd Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S579-S580, ISSN: 0009-7322
Chambers JC, Zhang W, Li Y, et al., 2009, Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels, NATURE GENETICS, Vol: 41, Pages: 1170-1172, ISSN: 1061-4036
Chambers JC, Zhang W, Zabaneh D, et al., 2009, Common genetic variation near melatonin receptor mtnr1b contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians, Diabetes, Vol: 58, Pages: 2703-2708, ISSN: 0012-1797
OBJECTIVE Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians.RESEARCH DESIGN AND METHODS We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians.RESULTS We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians.CONCLUSIONS Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.
Waller-Evans HE, Fearnside J, Argoud K, et al., 2009, Identification and characterisation of candidate genes in diet-induced non-alcoholic fatty liver disease in inbred mice, 45th Annual Meeting of the European-Association-for-the-Study-of-Diabetes, Publisher: SPRINGER, Pages: S259-S259, ISSN: 0012-186X
Elliott P, Chambers JC, Zhang W, et al., 2009, Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, Vol: 302, Pages: 37-48, ISSN: 0098-7484
Elliott P, Chambers JC, Zhang W, et al., 2009, GENETIC LOCI INFLUENCING C-REACTIVE PROTEIN LEVELS AND CORONARY HEART DISEASE RISK: RESULTS OF GENETIC ASSOCIATION AND MENDELIAN RANDOMISATION STUDY WITH META-ANALYSIS IN 80 614 PEOPLE, Annual Scientific Conference of the British-Cardiovascular-Society, Publisher: B M J PUBLISHING GROUP, Pages: A61-A61, ISSN: 1355-6037
Chambers JC, Zhang W, Sehmi J, et al., 2009, COMMON GENETIC VARIATION NEAR MTNR1B CONTRIBUTES TO RAISED PLASMA GLUCOSE AND INCREASED RISK OF TYPE-2 DIABETES AMONG INDIAN ASIANS, Annual Scientific Conference of the British-Cardiovascular-Society, Publisher: B M J PUBLISHING GROUP, Pages: A82-A82, ISSN: 1355-6037
Fearnside J, Waller-Evans H, Argoud K, et al., 2009, IDENTIFICATION OF CANDIDATE GENES IN DIET INDUCED NON-ALCOHOLIC FATTY LIVER DISEASE IN INBRED MICE, 44th Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S258-S258, ISSN: 0168-8278
Yuan X, Waterworth D, Perry JRB, et al., 2008, Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 83, Pages: 520-528, ISSN: 0002-9297
Zhang W, Zabaneh D, Balding D, et al., 2008, Are Indian Asians genetically homogeneous? Implications for genetic association studies, Annual Scientific Conference of the British-Cardiovascular-Society/British-Society-for-Cardiovascular-Research, Publisher: B M J PUBLISHING GROUP, Pages: A65-A65, ISSN: 1355-6037
Chambers JC, Elliott P, Scott J, et al., 2008, Genome-wide association study identifies mlxipl as a novel determinant of trigyceride levels in man, Annual Scientific Conference of the British-Cardiovascular-Society/British-Society-for-Cardiovascular-Research, Publisher: B M J PUBLISHING GROUP, Pages: A5-A5, ISSN: 1355-6037
Chambers JC, Zhang W, Zabaneh D, et al., 2008, Does genetic variation in FTO account for the increased risk of obesity and type 2 diabetes in UK Indian Asians?, Annual Scientific Conference of the British-Cardiovascular-Society/British-Society-for-Cardiovascular-Research, Publisher: B M J PUBLISHING GROUP, Pages: A58-A59, ISSN: 1355-6037
Chambers JC, Elliott P, Zabaneh D, et al., 2008, Common genetic variation near MC4R is associated with waist circumference and insulin resistance, NATURE GENETICS, Vol: 40, Pages: 716-718, ISSN: 1061-4036
Fearnside JF, Dumas M-E, Rothwell AR, et al., 2008, Phylometabonomic Patterns of Adaptation to High Fat Diet Feeding in Inbred Mice, PLOS ONE, Vol: 3, ISSN: 1932-6203
Kooner JS, Chambers JC, Aguilar-Salinas CA, et al., 2008, Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides, Nature Genetics
Scott J, 2007, The liver X receptor and atherosclerosis, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 357, Pages: 2195-2197, ISSN: 0028-4793
Chambers JC, Scott J, Hinds DA, et al., 2007, A genome-wide scan identifies novel and known DNA variants associated with component phenotypes of metabolic syndrome, 80th Annual Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 507-507, ISSN: 0009-7322
Seth A, Steel JH, Nichol D, et al., 2007, The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle, Cell Metabolism, Vol: 6, Pages: 236-245, ISSN: 1932-7420
Nuclear receptor signaling plays an important role in energy metabolism. In this study we demonstrate that the nuclear receptor corepressor RIP140 is a key regulator of metabolism in skeletal muscle. RIP140 is expressed in a fiber type-specific manner, and manipulation of its levels in null, heterozygous, and transgenic mice demonstrate that low levels promote while increased expression suppresses the formation of oxidative fibers. Expression profiling reveals global changes in the expression of genes implicated in both myofiber phenotype and metabolic functions. Genes involved in fattyacid oxidation, oxidative phosphorylation, and mitochondrial biogenesis are upregulated in the absence of RIP140. Analysis of cultured myofibers demonstrates that the changes in expression are intrinsic to muscle cells and that nuclear receptor-regulated genes are direct targets for repression by RIP140. Therefore RIP140 is an important signaling factor in the regulation of skeletal muscle function and physiology.
Zabaneh D, Chambers JC, Elliott P, et al., 2007, Estimating heritabilities and genetic correlations of insulin resistance and related metabolic traits in Indian families using a multivariate maximum likelihood approach, 16th Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: WILEY-LISS, Pages: 651-651, ISSN: 0741-0395
Toye AA, Dumas ME, Blancher C, et al., 2007, Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice, Diabetologia, Vol: 50, Pages: 1867-1879, ISSN: 0012-186X
Aims/hypothesis Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with diet-induced NAFLD. Materials and Methods Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD. Results In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD. Conclusions/interpretation Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to diet-induced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms. Electronic supplementary material The online version of this article (doi:10.1007/s00125-007-0738-5) contains supplementary material, which is available to authorised users.
Parry S, Ledger V, Tissot B, et al., 2007, Integrated mass spectrometric strategy for characterizing the glycans from glycosphingolipids and glycoproteins: direct identification of sialyl Le(x) in mice, GLYCOBIOLOGY, Vol: 17, Pages: 646-654, ISSN: 0959-6658
Griffin JL, Scott J, Nicholson JK, 2007, The influence of pharmacogenetics on fatty liver disease in the Wistar and Kyoto rats: A combined transcriptomic and metabonomic study, JOURNAL OF PROTEOME RESEARCH, Vol: 6, Pages: 54-61, ISSN: 1535-3893
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.