190 results found
Gerber RT, ASP S, Sachdev B, et al., 2015, Reproducibilty of the syntax score in a real world setting: implications for the choice of contemporary revascularisation strategy, BCS, Pages: A20-A21
Yaghootkar H, Scott RA, White CC, et al., 2014, Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes, Diabetes, Vol: 63, Pages: 4369-4377, ISSN: 0012-1797
The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy—a reduction in subcutaneous adipose tissue—it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin–based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10−29), lower HDL cholesterol (β = −0.020; P = 7 × 10−37), greater hepatic steatosis (β = 0.021; P = 3 × 10−4), higher alanine transaminase (β = 0.002; P = 3 × 10−5), lower sex-hormone-binding globulin (β = −0.010; P = 9 × 10−13), and lower adiponectin (β = −0.015; P = 2 × 10−26). The same risk alleles were associated with lower BMI (per-allele β = −0.008; P = 7 × 10−8) and increased visceral-to-subcutaneous adipose tissue ratio (β = −0.015; P = 6 × 10−7). Individuals carrying ≥17 fasting insulin–raising alleles (5.5% population) were slimmer (0.30 kg/m2) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5
Wood AR, Esko T, Yang J, et al., 2014, Defining the role of common variation in the genomic and biological architecture of adult human height, Nature Genetics, Vol: 46, Pages: 1173-1186, ISSN: 1546-1718
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Xi B, Takeuchi F, Meirhaeghe A, et al., 2014, Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis, CLINICAL ENDOCRINOLOGY, Vol: 81, Pages: 702-710, ISSN: 0300-0664
Chen L, Kostadima M, Martens JHA, et al., 2014, Transcriptional diversity during lineage commitment of human blood progenitors, SCIENCE, Vol: 345, Pages: 1580-+, ISSN: 0036-8075
The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
The Indian Asian population accounts for a fifth of all global deaths from coronary heart disease (CHD). CHD deaths on the Indian subcontinent have doubled since 1990, and are predicted to rise a further 50% by 2030. Reasons underlying the increased CHD mortality among Indian Asians remain unknown. Although conventional cardiovascular risk factors contribute to CHD in Indian Asians as in other populations, these do not account for their increased risk. Type-2 diabetes, insulin resistance and related metabolic disturbances are more prevalent amongst Indian Asians than Europeans, and have been proposed as major determinants of higher CHD risk among Indian Asians. However, this view is not supported by prospective data. Genome-wide association studies have not identified differences in allele frequencies or effect sizes in known loci to explain the increased CHD risk in Indian Asians. Limited knowledge of mechanisms underlying higher CHD risk amongst Indian Asians presents a major obstacle to reducing the burden of CHD in this population. Systems biology approaches such as genomics, epigenomics, metabolomics and transcriptomics, provide a non-biased approach for discovery of novel biomarkers and disease pathways underlying CHD. Incorporation of these 'omic' approaches in prospective Indian Asian cohorts such as the London Life Sciences Population Study (LOLIPOP) provide an exciting opportunity for the identification of new risk factors underlying CHD in this high risk population.
Al-Hussaini A, Kooner JS, John C, 2013, Novel Metabolic Biomarkers Predict Cardiovascular Mortality, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Do R, Willer CJ, Schmidt EM, et al., 2013, Common variants associated with plasma triglycerides and risk for coronary artery disease, Nature Genetics, Vol: 45, Pages: 1345-1352, ISSN: 1061-4036
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10−8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Willer CJ, Schmidt EM, Sengupta S, et al., 2013, Discovery and refinement of loci associated with lipid levels, Nature Genetics, Vol: 45, Pages: 1274-1283, ISSN: 1061-4036
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
O'Seaghdha CM, Wu H, Yang Q, et al., 2013, Meta-analysis of genome-wide association studies identifies six new loci for serum calcium concentrations, PLoS Genetics, Vol: 9, Pages: 1-13, ISSN: 1553-7390
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Sabater-Lleal M, Huang J, Chasman D, et al., 2013, Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease, CIRCULATION, Vol: 128, Pages: 1310-1324, ISSN: 0009-7322
den Hoed M, Eijgelsheim M, Esko T, et al., 2013, Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders, NATURE GENETICS, Vol: 45, Pages: 621-+, ISSN: 1061-4036
Wang X, Chua H-X, Chen P, et al., 2013, Comparing methods for performing trans-ethnic meta-analysis of genome-wide association studies, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 2303-2311, ISSN: 0964-6906
Koettgen A, Albrecht E, Teumer A, et al., 2013, Genome-wide association analyses identify 18 new loci associated with serum urate concentrations, NATURE GENETICS, Vol: 45, Pages: 145-154, ISSN: 1061-4036
Deloukas P, Kanoni S, Willenborg C, et al., 2013, Large-scale association analysis identifies new risk loci for coronary artery disease, NATURE GENETICS, Vol: 45, Pages: 25-U52, ISSN: 1061-4036
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
Huang J, Sabater-Lleal M, Asselbergs FW, et al., 2012, Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation, BLOOD, Vol: 120, Pages: 4873-4881, ISSN: 0006-4971
Okada Y, Sim X, Go MJ, et al., 2012, Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations, NATURE GENETICS, Vol: 44, Pages: 904-+, ISSN: 1061-4036
Sarwar N, Butterworth AS, Freitag DF, et al., 2012, Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies, LANCET, Vol: 379, Pages: 1205-1213, ISSN: 0140-6736
Dastani Z, Hivert M-F, Timpson N, et al., 2012, Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals, PLOS Genetics, Vol: 8, ISSN: 1553-7390
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inverselyassociated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wideassociation studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. Weidentified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.561028–1.2610243). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, andN = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samplesrevealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations afteraccounting for multiple testing (p,361024). We next developed a multi-SNP genotypic risk score to test the associationof adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This riskscore was associated with increased risk of T2D (p = 4.361023, n = 22,044), increased triglycerides (p = 2.6610214,n = 93,440), increased waist-to-hip ratio (p = 1.861025, n = 77,167), increased glucose two hours post oral glucosetolerance testing (p = 4.461023, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDLcholesterolconcentrations (p = 4.5610213, n = 96,748) and decreased BMI (p = 1.461024, n = 121,335). These findingsidentify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers ofinsulin resistance.
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
Chambers JC, Zhang W, Sehmi J, et al., 2011, Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma, NATURE GENETICS, Vol: 43, Pages: 1131-1138, ISSN: 1061-4036
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
Kooner JS, Saleheen D, Sim X, et al., 2011, Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci, NATURE GENETICS, Vol: 43, Pages: 984-U94, ISSN: 1061-4036
Wain LV, Verwoert GC, O'Reilly PF, et al., 2011, Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure, NATURE GENETICS, Vol: 43, Pages: 1005-U122, ISSN: 1061-4036
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans1,2,3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10−8 to P = 2.3 × 10−13) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Kilpelainen TO, Zillikens MC, Stancakova A, et al., 2011, Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile, NATURE GENETICS, Vol: 43, Pages: 753-U58, ISSN: 1061-4036
Sehmi J, Saleheen D, Yeo IY, et al., 2011, A genome-wide association study in Indian Asians identifies five novel genetic variants for type-2 diabetes, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 357-357, ISSN: 0195-668X
Das D, Sehmi J, Ahmed N, et al., 2011, Comparison of known genetic variants to coronary heart disease risk between Indian Asians and Europeans, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 652-652, ISSN: 0195-668X
Sehmi J, Yeo IY, Salaheen S, et al., 2011, Contribution of known genetic variants to increased risk of type-2 diabetes in Indian Asians, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 673-673, ISSN: 0195-668X
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