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1. Demonstration of the presence of the 'deleted' MIR122 gene in HepG2 cells.

Author

Ibrahim A Y Hamad, Yue Fei, Anastasia Z Kalea, Dan Yin, Andrew J P Smith, Jutta Palmen, Steve E Humphries, Philippa J Talmud, and Ann P Walker

Subjects
Medicine, Science
Abstract

MicroRNA 122 (miR-122) is highly expressed in the liver where it influences diverse biological processes and pathways, including hepatitis C virus replication and metabolism of iron and cholesterol. It is processed from a long non-coding primary transcript (~7.5 kb) and the gene has two evolutionarily-conserved regions containing the pri-mir-122 promoter and pre-mir-122 hairpin region. Several groups reported that the widely-used hepatocytic cell line HepG2 had deficient expression of miR-122, previously ascribed to deletion of the pre-mir-122 stem-loop region. We aimed to characterise this deletion by direct sequencing of 6078 bp containing the pri-mir-122 promoter and pre-mir-122 stem-loop region in HepG2 and Huh-7, a control hepatocytic cell line reported to express miR-122, supported by sequence analysis of cloned genomic DNA. In contrast to previous findings, the entire sequence was present in both cell lines. Ten SNPs were heterozygous in HepG2 indicating that DNA was present in two copies. Three validation isolates of HepG2 were sequenced, showing identical genotype to the original in two, whereas the third was different. Investigation of promoter chromatin status by FAIRE showed that Huh-7 cells had 6.2 ± 0.19- and 2.7 ± 0.01- fold more accessible chromatin at the proximal (HNF4α-binding) and distal DR1 transcription factor sites, compared to HepG2 cells (p=0.03 and 0.001, respectively). This was substantiated by ENCODE genome annotations, which showed a DNAse I hypersensitive site in the pri-mir-122 promoter in Huh-7 that was absent in HepG2 cells. While the origin of the reported deletion is unclear, cell lines should be obtained from a reputable source and used at low passage number to avoid discrepant results. Deficiency of miR-122 expression in HepG2 cells may be related to a relative deficiency of accessible promoter chromatin in HepG2 versus Huh-7 cells.

Published
2015
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2. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development. [v2; ref status: indexed, http://f1000r.es/2ys]

Author

Varsha K Khodiyar, Doug Howe, Philippa J Talmud, Ross Breckenridge, and Ruth C Lovering

Subjects
Bioinformatics, Pattern Formation, Medicine, Science
Abstract

For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’. ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development. We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging. We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging. This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.

Published
2014
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3. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development. [v1; ref status: indexed, http://f1000r.es/28b]

Author

Varsha K Khodiyar, Doug Howe, Philippa J Talmud, Ross Breckenridge, and Ruth C Lovering

Subjects
Bioinformatics, Pattern Formation, Medicine, Science
Abstract

For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’. ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development. We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging. We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging. This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.

Published
2013
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4. Association of TERC and OBFC1 haplotypes with mean leukocyte telomere length and risk for coronary heart disease.

Author

Cécilia G Maubaret, Klelia D Salpea, Casey E Romanoski, Lasse Folkersen, Jackie A Cooper, Coralea Stephanou, Ka Wah Li, Jutta Palmen, Anders Hamsten, Andrew Neil, Jeffrey W Stephens, Aldons J Lusis, Per Eriksson, Philippa J Talmud, Steve E Humphries, Simon Broome Research Group, and EARSII consortium

Subjects
Medicine, Science
Abstract

To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology.Four SNPs at three loci BICD1 (rs2630578 GγC), 18q12.2 (rs2162440 GγT), and OBFC1 (rs10786775 CγG, rs11591710 AγC) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 CγG, rs10936601G>T and rs16847897 GγC) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method.Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (β=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61-0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61-0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing.Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects.

Published
2013
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5. Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.

Author

Tina Shah, Jorgen Engmann, Caroline Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom Gaunt, Michael V Holmes, Helen Warren, Daniel I Swerdlow, Teri-Louise Davies, Fotios Drenos, Jackie Cooper, Reecha Sofat, Mark Caulfield, Shah Ebrahim, Debbie A Lawlor, Philippa J Talmud, Steve E Humphries, Christine Power, Elina Hypponen, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Claudia Langenberg, Yoav Ben-Shlomo, Ian N Day, Peter Whincup, Richard Morris, Mark W J Strachan, Jacqueline Price, Meena Kumari, Mika Kivimaki, Vincent Plagnol, Frank Dudbridge, John C Whittaker, Juan P Casas, Aroon D Hingorani, and UCLEB Consortium

Subjects
Medicine, Science
Abstract

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.

Published
2013
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6. Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.

Author

Audrey C Papp, Julia K Pinsonneault, Danxin Wang, Leslie C Newman, Yan Gong, Julie A Johnson, Carl J Pepine, Meena Kumari, Aroon D Hingorani, Philippa J Talmud, Sonia Shah, Steve E Humphries, and Wolfgang Sadee

Subjects
Medicine, Science
Abstract

Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5-7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4 × 10(-5), allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8 × 10(-10)) and intron 8 polymorphism rs9930761-T>C (5.6 × 10(-8)) (in high linkage disequilibrium with allele frequencies 6-7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6 × 10(-28) and rs5883 p = 8.6 × 10(-10), adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29-4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.

Published
2012
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7. Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays.

Author

Andrew J P Smith, Philip Howard, Sonia Shah, Per Eriksson, Stefan Stender, Claudia Giambartolomei, Lasse Folkersen, Anne Tybjærg-Hansen, Meena Kumari, Jutta Palmen, Aroon D Hingorani, Philippa J Talmud, and Steve E Humphries

Subjects
Genetics, QH426-470
Abstract

Following the widespread use of genome-wide association studies (GWAS), focus is turning towards identification of causal variants rather than simply genetic markers of diseases and traits. As a step towards a high-throughput method to identify genome-wide, non-coding, functional regulatory variants, we describe the technique of allele-specific FAIRE, utilising large-scale genotyping technology (FAIRE-gen) to determine allelic effects on chromatin accessibility and regulatory potential. FAIRE-gen was explored using lymphoblastoid cells and the 50,000 SNP Illumina CVD BeadChip. The technique identified an allele-specific regulatory polymorphism within NR1H3 (coding for LXR-α), rs7120118, coinciding with a previously GWAS-identified SNP for HDL-C levels. This finding was confirmed using FAIRE-gen with the 200,000 SNP Illumina Metabochip and verified with the established method of TaqMan allelic discrimination. Examination of this SNP in two prospective Caucasian cohorts comprising 15,000 individuals confirmed the association with HDL-C levels (combined beta = 0.016; p = 0.0006), and analysis of gene expression identified an allelic association with LXR-α expression in heart tissue. Using increasingly comprehensive genotyping chips and distinct tissues for examination, FAIRE-gen has the potential to aid the identification of many causal SNPs associated with disease from GWAS.

Published
2012
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8. Functional analysis of two PLA2G2A variants associated with secretory phospholipase A2-IIA levels.

Author

Holly J Exeter, Lasse Folkersen, Jutta Palmen, Anders Franco-Cereceda, Jackie A Cooper, Anastasia Z Kalea, Ferdinand Van't Hooft, Per Eriksson, Steve E Humphries, and Philippa J Talmud

Subjects
Medicine, Science
Abstract

Secretory phospholipase A2 group IIA (sPLA2-IIA) has been identified as a biomarker of atherosclerosis in observational and animal studies. The protein is encoded by the PLA2G2A gene and the aim of this study was to test the functionality of two PLA2G2A non-coding SNPs, rs11573156 C>G and rs3767221 T>G where the rare alleles have been previously associated with higher and lower sPLA2-IIA levels respectively.Luciferase assays, electrophoretic mobility shift assays (EMSA), and RNA expression by RT-PCR were used to examine allelic differences. For rs3767221 the G allele showed ∼55% lower luciferase activity compared to the T allele (T = 62.1 (95% CI 59.1 to 65.1) G = 27.8 (95% CI 25.0 to 30.6), p = 1.22×10⁻³⁵, and stronger EMSA binding of a nuclear protein compared to the T-allele. For rs11573156 C >G there were no luciferase or EMSA allelic differences seen. In lymphocyte cell RNA, from individuals of known rs11573156 genotype, there was no allelic RNA expression difference for exons 5 and 6, but G allele carriers (n = 7) showed a trend to lower exon 1-2 expression compared to CC individuals. To take this further, in the ASAP study (n = 223), an rs11573156 proxy (r² = 0.91) showed ∼25% higher liver expression of PLA2G2A (1.67×10⁻¹⁷) associated with the G allele. However, considering exon specific expression, the association was greatly reduced for exon 2 (4.5×10⁻⁵) compared to exons 3-6 (10⁻¹⁰ to 10⁻²⁰), suggesting rs11573156 G allele-specific exon 2 skipping.Both SNPs are functional and provide useful tools for Mendelian Randomisation to determine whether the relationship between sPLA2-IIA and coronary heart disease is causal.

Published
2012
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9. The impact of focused Gene Ontology curation of specific mammalian systems.

Author

Yasmin Alam-Faruque, Rachael P Huntley, Varsha K Khodiyar, Evelyn B Camon, Emily C Dimmer, Tony Sawford, Maria J Martin, Claire O'Donovan, Philippa J Talmud, Peter Scambler, Rolf Apweiler, and Ruth C Lovering

Subjects
Medicine, Science
Abstract

The Gene Ontology (GO) resource provides dynamic controlled vocabularies to provide an information-rich resource to aid in the consistent description of the functional attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org). System-focused projects, such as the Renal and Cardiovascular GO Annotation Initiatives, aim to provide detailed GO data for proteins implicated in specific organ development and function. Such projects support the rapid evaluation of new experimental data and aid in the generation of novel biological insights to help alleviate human disease. This paper describes the improvement of GO data for renal and cardiovascular research communities and demonstrates that the cardiovascular-focused GO annotations, created over the past three years, have led to an evident improvement of microarray interpretation. The reanalysis of cardiovascular microarray datasets confirms the need to continue to improve the annotation of the human proteome.GO ANNOTATION DATA IS FREELY AVAILABLE FROM: ftp://ftp.geneontology.org/pub/go/gene-associations/

Published
2011
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10. Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.

Author

Emily Rose Holzinger, Shefali S. Verma, Carrie Colleen Buchanan Moore, Molly A. Hall, Rishika De, Diane Gilbert-Diamond, Matthew B. Lanktree, Nathan Pankratz, Antoinette Amuzu, Amber Burt, Caroline Dale, Scott M. Dudek, Clement E. Furlong, Tom R. Gaunt, Daniel Seung Kim, Helene Riess, Suthesh Sivapalaratnam, Vinicius Tragante, Erik P. A. van Iperen, Ariel Brautbar, David S. Carrell, David R. Crosslin, Gail P. Jarvik, Helena Kuivaniemi, Iftikhar J. Kullo, Eric B. Larson, Laura J. Rasmussen-Torvik, Gerard Tromp, Jens Baumert, Karen J. Cruickshanks, Martin Farrall, Aroon D. Hingorani, G. K. Hovingh, Marcus E. Kleber, Barbara E. Klein, Ronald Klein, Wolfgang Koenig, Leslie A. Lange, Winfried März, Kari E. North, N. Charlotte Onland-Moret, Alex P. Reiner, Philippa J. Talmud, Yvonne T. van der Schouw, James G. Wilson, Mika Kivimäki, Meena Kumari, Jason H. Moore, Fotios Drenos, Folkert W. Asselbergs, Brendan J. Keating, and Marylyn D. Ritchie

Published
2017
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11. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development. [version 2; referees: 2 approved]

Author

Varsha K Khodiyar, Doug Howe, Philippa J Talmud, Ross Breckenridge, and Ruth C Lovering

Subjects
Research Article, Articles, Bioinformatics, Pattern Formation, Early heart development, heart jogging, Gene Ontology, Orthology
Abstract

For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’. ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development. We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging. We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging. This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.

Published
2014
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12. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development. [version 1; referees: 2 approved]

Author

Varsha K Khodiyar, Doug Howe, Philippa J Talmud, Ross Breckenridge, and Ruth C Lovering

Subjects
Research Article, Articles, Bioinformatics, Pattern Formation, Early heart development, heart jogging, Gene Ontology, Orthology
Abstract

For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’. ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development. We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging. We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging. This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.

Published
2013
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13. Deciphering the Causal Role of sPLA2s and Lp-PLA2 in Coronary Heart Disease

Author

Michael V. Holmes and Philippa J. Talmud

Subjects
Indoles, Phospholipase A2 Inhibitors, Coronary Disease, Acetates, Pharmacology, Biology, Bioinformatics, law.invention, chemistry.chemical_compound, Randomized controlled trial, law, Darapladib, Oximes, Mendelian randomization, Animals, Humans, Molecular Targeted Therapy, Phospholipases A2, Secretory, Keto Acids, Clinical trial, Treatment Outcome, Drug development, chemistry, Benzaldehydes, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Biomarker (medicine), Varespladib, Observational study, Cardiology and Cardiovascular Medicine, Biomarkers, Signal Transduction
Abstract

Over the last 10 to 15 years, animal and human observational studies have identified elevated levels of both proinflammatory secretory phospholipase A2-IIA and lipoprotein-associated phospholipase A2 as potential risk factors for coronary heart disease. However, Mendelian randomization, a genetic tool to test causality of a biomarker, and phase III randomized controlled trials of inhibitors of theses enzymes (varespladib and darapladib) converged to indicate that elevated levels are unlikely to be themselves causal of coronary heart disease and that inhibition had little or no clinical utility. The concordance of findings from Mendelian randomization and clinical trials suggests that for these 2 drugs, and for other novel biomarkers in future, validation of potential therapeutic targets by genetic studies (such as Mendelian randomization) before embarking on costly phase III randomized controlled trials could increase efficiency and offset the high risk of drug development, thereby facilitating discovery of new therapeutics and mitigating against the exuberant costs of drug development.

Published
2015
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14. APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis

Author

Philippa J. Talmud, Montse Guardiola, Emilio Ros, J. Ribalta, Núria Plana, Lluís Masana, Montserrat Cofán, Ana Cenarro, Isabel De Castro-Orós, and Fernando Civeira

Subjects
Adult, Carotid Artery Diseases, Male, Heterozygote, medicine.medical_specialty, Very low-density lipoprotein, Magnetic Resonance Spectroscopy, Waist, Population, Locus (genetics), Comorbidity, Biology, Carotid Intima-Media Thickness, Subclass, Young Adult, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Apolipoproteins A, Triglycerides, Dyslipidemias, education.field_of_study, Homozygote, Genetic Variation, Middle Aged, Overweight, medicine.disease, Lipoproteins, LDL, Phenotype, Endocrinology, Apolipoprotein A-V, Spain, Asymptomatic Diseases, Female, Waist Circumference, Metabolic syndrome, Cardiology and Cardiovascular Medicine, Biomarkers, Lipoprotein
Abstract

Triglycerides (TG) are the initiators of the metabolic changes leading to the atherogenic dyslipidemia, which is a major inducer of atherosclerosis as a result of quantitative and qualitative changes in lipoprotein subclass distributions. We hypothesized that variation at the of APOA5 gene locus, encoding apoAV, a key regulator of TG levels, significantly affect lipoprotein subclass distributions toward a more atherogenic pattern in both hyperTG patients and dyslipemic patients.We recruited four hundred and twenty-two subjects attending a Lipid Clinic, prior to lipid-lowering treatment. We genotyped two APOA5 variants, rs662799 (-1131TC) and rs3135506 (S19W). Circulating lipoproteins were determined by nuclear magnetic resonance (NMR). Intima-media thickness (IMT) was evaluated using B-mode ultrasound.Carriers of the rare alleles of rs662799 and rs3135506 compared to common allele homozygotes, had a significantly proatherogenic profile of the VLDL and LDL subclasses, resulting in increased concentrations of the proatherogenic subclasses, large VLDLs (+133%, p0.001) and small LDLs (+34%, p=0.014). Significant changes in smaller HDL (+71%, p=0.032), as well as an 18% decrease in large HDL (p=0.046), were also been observed. This atherogenic NMR subclass distribution was significantly associated with increased carotid IMT. The observed effects were significantly stronger in patients with a BMI≥25 kg/m2 and in male and female patients with a waist circumference≥90 cm or ≥85 cm, respectively.In a dyslipemic population, genetic variants of APOA5 modulate lipoprotein subclass distributions, inducing an atherogenic profile associated with IMT defined subclinical atherosclerosis.

Published
2015
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15. Genetically determined telomeres shortening is associated with carotid atherosclerosis progression and increased incidence of cardiovascular events

Author

Andrea Baragetti, Alberico L. Catapano, S. E. Humphries, Philippa J. Talmud, Jutta Palmen, Liliana Grigore, Katia Garlaschelli, and Giuseppe Danilo Norata

Subjects
Carotid Artery Diseases, 0301 basic medicine, Carotid atherosclerosis, medicine.medical_specialty, Pathology, Statistics as Topic, 030204 cardiovascular system & hematology, Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Telomerase, Telomere Shortening, Asymptomatic Diseases, business.industry, Incidence, Disease progression, Membrane Proteins, Neoplasm Proteins, Telomere, 030104 developmental biology, Intima-media thickness, Cardiovascular Diseases, Disease Progression, Cardiology, RNA, Cardiology and Cardiovascular Medicine, business
Published
2016
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16. Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries

Author

Mary Aderayo Bamimore, Jeanine E. Roeters van Lennep, Giuliana Fortunato, Vasiliki Mollaki, Eran Leitersdorf, Antonietta D'Angelo, Sonia Shah, Euridiki Drogari, Philippa J. Talmud, Steve E. Humphries, Albert Wiegman, Mahtab Sharifi, Małgorzata Waluś-Miarka, Maria Nicoletta D'Agostino, KaWah Li, Paolo Rubba, Monique T. Mulder, Ros Whittall, Jackie A. Cooper, Ronen Durst, Marta Futema, Olivia Goldberg, Robert A. Hegele, Eric J.G. Sijbrands, Joep C. Defesche, John C. Whittaker, Internal Medicine, Futema, M, Shah, S, Cooper, Ja, Li, K, Whittall, Ra, Sharifi, M, Goldberg, O, Drogari, E, Mollaki, V, Wiegman, A, Defesche, J, D'Agostino, MARIA NICOLETTA, D'Angelo, A, Rubba, PAOLO OSVALDO FEDERICO, Fortunato, Giuliana, Walu?? Miarka, M, Hegele, Ra, Aderayo Bamimore, M, Durst, R, Leitersdorf, E, Mulder, Mt, Roeters van Lennep, Je, Sijbrands, Ej, Whittaker, Jc, Talmud, Pj, Humphries, S. E., Paediatric Metabolic Diseases, ACS - Amsterdam Cardiovascular Sciences, and Experimental Vascular Medicine

Subjects
Adult, Male, Canada, Multifactorial Inheritance, Adolescent, Clinical Biochemistry, Single-nucleotide polymorphism, Familial hypercholesterolemia, Biology, medicine.disease_cause, Bioinformatics, Polymorphism, Single Nucleotide, Article, Cohort Studies, Hyperlipoproteinemia Type II, Young Adult, chemistry.chemical_compound, Risk Factors, Polymorphism (computer science), medicine, Humans, Israel, Allele, Child, Gene, Alleles, Apolipoproteins B, Genetics, Mutation, Cholesterol, Serine Endopeptidases, Biochemistry (medical), Case-control study, Cholesterol, LDL, Middle Aged, medicine.disease, Europe, ROC Curve, Receptors, LDL, chemistry, Case-Control Studies, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertases, Proprotein Convertase 9
Abstract

BACKGROUND Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12–single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M–), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M– and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M– cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10−16). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS A 6-SNP LDL-C score consistently distinguishes FH/M– patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.

Published
2015
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17. Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels

Author

Michael V, Holmes, Holly J, Exeter, Lasse, Folkersen, Christopher P, Nelson, Montse, Guardiola, Jackie A, Cooper, Reecha, Sofat, S Matthijs, Boekholdt, Kay-Tee, Khaw, Ka-Wah, Li, Andrew J P, Smith, Ferdinand, Van't Hooft, Per, Eriksson, Anders, Franco-Cereceda, Folkert W, Asselbergs, Jolanda M A, Boer, N Charlotte, Onland-Moret, Marten, Hofker, Jeanette, Erdmann, Mika, Kivimaki, Meena, Kumari, Alex P, Reiner, Brendan J, Keating, Steve E, Humphries, Aroon D, Hingorani, Ziad, Mallat, Nilesh J, Samani, Philippa J, Talmud, Alastair S, Hall, Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
Genotype, Mendelian randomization analysis, Coronary Disease, Biology, Bioinformatics, HEALTHY-MEN, Polymorphism, Single Nucleotide, Article, EPIC-NORFOLK, Group V Phospholipases A2, Pathogenesis, EVENTS, Mendelian randomization, Genetics, Humans, SNP, ARTERY-DISEASE, Allele, Alleles, Genetics (clinical), RISK, GROUP-V, Case-control study, Mendelian Randomization Analysis, Odds ratio, ASSOCIATION, Isoenzymes, ATHEROSCLEROSIS, CARDIOVASCULAR-DISEASE, Case-Control Studies, A(2), Cardiology and Cardiovascular Medicine
Abstract

Background— Secretory phospholipase A 2 (sPLA 2 ) enzymes are considered to play a role in atherosclerosis. sPLA 2 activity encompasses several sPLA 2 isoenzymes, including sPLA 2 -V. Although observational studies show a strong association between elevated sPLA 2 activity and CHD, no assay to measure sPLA 2 -V levels exists, and the only evidence linking the sPLA 2 -V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA 2 -V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA 2 -V in coronary heart disease (CHD) pathogenesis. Methods and Results— Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA 2 -V levels. We tested the association of this SNP with sPLA 2 activity and CHD events in 4 prospective and 14 case–control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression ( P =5.1×10 −6 ). There was no association of rs525380C>A with plasma sPLA 2 activity (difference in geometric mean of sPLA 2 activity per rs525380 A-allele 0.4% (95% confidence intervals [−0.9%, 1.6%]; P =0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P =0.20). Conclusions— This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA 2 -V levels) and CHD events. The evidence does not support a causal role for sPLA 2 -V in CHD.

Published
2014
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18. Gene-Centric Analysis Identifies Variants Associated With Interleukin-6 Levels and Shared Pathways With Other Inflammation Markers

Author

Meena Kumari, John C. Whittaker, Michael V. Holmes, Reecha Sofat, Juan P. Casas, Tom R. Gaunt, Sonia Shah, Aroon D. Hingorani, Ian N. M. Day, Daniel I. Swerdlow, Mika Kivimäki, Tina Shah, Delilah Zabaneh, Philippa J. Talmud, and Steve E. Humphries

Subjects
Male, Nonsynonymous substitution, Genotype, Genome-wide association study, Coronary Artery Disease, Disease, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Autoimmune Diseases, Risk Factors, ABO blood group system, Genetics, Humans, Medicine, Risk factor, Allele, Interleukin 6, Alleles, Genetics (clinical), Aged, Inflammation, biology, Interleukin-6, business.industry, C-reactive protein, Middle Aged, Receptors, Interleukin-6, C-Reactive Protein, Phenotype, Genetic Loci, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Genome-Wide Association Study
Abstract

Background— Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. Methods and Results— We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women’s Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci ( IL6R/TDRD10 , HLA-DRB1 , BUD13 , SEZ6L , IL1RN , TRIB3 , and ABO ) were associated with IL-6 ( P –5 ), although none were associated with the IL6 gene itself. With the exception of TRIB3 , all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r 2 >0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration ( P –5 ). An IL-6–specific weighted allele score explained 2% of the variance of log IL-6 levels ( P =2.4410 –22 ) in Whitehall II and 1% ( P =1.910 –8 ) in British Women’s Heart and Health Studies. Conclusions— Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases.

Published
2013
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19. Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals

Author

Barbara E.K. Klein, Molly A. Hall, Eric B. Larson, Gerard Tromp, G K Hovingh, Carrie B. Moore, Suthesh Sivapalaratnam, Erik P A Van Iperen, Marcus E. Kleber, Yvonne T. van der Schouw, Antoinette Amuzu, Jens Baumert, Mika Kivimäki, Ariel Brautbar, Alexander P. Reiner, Emily R. Holzinger, Philippa J. Talmud, Scott M. Dudek, Ronald Klein, Gail P. Jarvik, Caroline Dale, Leslie A. Lange, N. Charlotte Onland-Moret, Fotios Drenos, Rishika De, Shefali S. Verma, Daniel Seung Kim, Aroon D. Hingorani, Martin Farrall, Brendan J. Keating, Kari E. North, Tom R. Gaunt, Marylyn D. Ritchie, Vinicius Tragante, Helena Kuivaniemi, David Carrell, Iftikhar J. Kullo, Matthew B. Lanktree, Jason H. Moore, Laura J. Rasmussen-Torvik, James G. Wilson, David R. Crosslin, Nathan Pankratz, Winfried Mӓrz, Meena Kumari, Amber A. Burt, Diane Gilbert-Diamond, Karen J. Cruickshanks, Folkert W. Asselbergs, Clement E. Furlong, Helene Riess, Wolfgang Koenig, Vascular Medicine, APH - Methodology, Graduate School, Epidemiology and Data Science, ACS - Amsterdam Cardiovascular Sciences, and ACS - Atherosclerosis & ischemic syndromes

Subjects
0301 basic medicine, Interactions, Single-nucleotide polymorphism, Genome-wide association study, lcsh:Analysis, Quantitative trait locus, Biology, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Computational Genetics, Genetic Epidemiology, Genetics, Lipids, 570 Life sciences, 03 medical and health sciences, 0302 clinical medicine, Journal Article, SNP, Genetic epidemiology, Gene, Molecular Biology, Research, lcsh:QA299.6-433, Computer Science Applications, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, Multiple comparisons problem, Epistasis, lcsh:R858-859.7, Computational genetics, lipids (amino acids, peptides, and proteins), 030217 neurology & neurosurgery
Abstract

Background The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). Results Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p

Published
2017

20. Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis

Author

Elena Tremoli, Fabrizio Veglia, John C. Whittaker, Mika Kivimäki, Karl Gertow, Claudia Langenberg, Damiano Baldassarre, Meena Kumari, Michael V. Holmes, Daniel I. Swerdlow, Ulf de Faire, Nicholas J. Wareham, Rona J. Strawbridge, Anders Hamsten, John E. Deanfield, Aroon D. Hingorani, Sonia Shah, Juan-Pablo Casas, Philippa J. Talmud, Steve E. Humphries, Fotios Drenos, Bengt Sennblad, and Bruna Gigante

Subjects
Carotid Artery Diseases, Male, medicine.medical_specialty, Blood lipids, Single-nucleotide polymorphism, Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Apolipoproteins E, Risk Factors, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Prospective Studies, Prospective cohort study, Triglycerides, Genetics (clinical), Aged, Cholesterol, business.industry, Surrogate endpoint, Cholesterol, HDL, Mendelian Randomization Analysis, Cholesterol, LDL, Middle Aged, Endocrinology, chemistry, Intima-media thickness, Cardiology, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, business
Abstract

Background— Carotid intima–media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease events. Statins reduce progression of CIMT and coronary heart disease risk in proportion to the reduction in low-density lipoprotein cholesterol. However, interventions targeting triglycerides (TGs) or high-density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and coronary heart disease risk, making it uncertain whether such agents are ineffective for coronary heart disease prevention or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects. We aimed to determine the causal association among the 3 major blood lipid fractions and common CIMT using mendelian randomization analysis. Methods and Results— Genetic scores specific for low-density lipoprotein cholesterol, HDL-C, and TGs were derived based on single nucleotide polymorphisms from a gene-centric array in ≈5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in >100 000 individuals (Global Lipids Genetic Consortium scores). These were used as instruments in a mendelian randomization analysis in 2 prospective cohort studies. A genetically predicted 1 mmol/L higher low-density lipoprotein cholesterol concentration was associated with a higher common CIMT by 0.03 mm (95% confidence interval, 0.01–0.04) and 0.04 mm (95% confidence interval, 0.02–0.06) based on the Cardiochip and Global Lipids Genetic Consortium scores, respectively. HDL-C and TGs were not causally associated with CIMT. Conclusions— Our findings confirm a causal relationship between low-density lipoprotein cholesterol and CIMT but not with HDL-C and TGs. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and TGs is questionable and requires further study.

Published
2013
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21. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Author

Nicholas J. Timpson, Klaudia Walter, Josine L. Min, Ioanna Tachmazidou, Giovanni Malerba, So Youn Shin, Lu Chen, Marta Futema, Lorraine Southam, Valentina Iotchkova, Jie Huang, Yasin Memari, Shane McCarthy, Petr Danecek, Dawn Muddyman, Massimo Mangino, Cristina Menni, John R. B. Perry, Susan M. Ring, Amadou Gaye, George Dedoussis, Aliki Eleni Farmaki, Paul Burton, Philippa J. Talmud, Giovanni Gambaro, Tim D. Spector, George Davey Smith, Richard Durbin, J. Brent Richards, Steve E. Humphries, Eleftheria Zeggini, Nicole Soranzo, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Jeffrey C. Barrett, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day Williams, Ian N. M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Louise Gallagher, Tom Gaunt, Matthias Geihs, Daniel Geschwind, Celia Greenwood, Heather Griffin, Detelina Grozeva, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Matthew E. Hurles, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Lotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Josine Min, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, John Perry, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Lucy Raymond, Karola Rehnström, Brent Richards, Susan Ring, Graham R. S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, Hasheem Shihab, David Skuse, Kerrin Small, Olivera Spasic Boskovic, Tim Spector, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Gabriela Surdulescu, Jaana Suvisaari, Ionna Tachmazidou, Nicholas Timpson, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Parthiban Vijayarangakannan, Peter M. Visscher, Louise V. Wain, James T. R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Scott G. Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Hou Feng Zheng, COCCA, MASSIMILIANO, Nicholas J., Timpson, Klaudia, Walter, Josine L., Min, Ioanna, Tachmazidou, Giovanni, Malerba, So Youn, Shin, Lu, Chen, Marta, Futema, Lorraine, Southam, Valentina, Iotchkova, Cocca, Massimiliano, Jie, Huang, Yasin, Memari, Shane, Mccarthy, Petr, Danecek, Dawn, Muddyman, Massimo, Mangino, Cristina, Menni, John R. B., Perry, Susan M., Ring, Amadou, Gaye, George, Dedoussi, Aliki Eleni, Farmaki, Paul, Burton, Philippa J., Talmud, Giovanni, Gambaro, Tim D., Spector, George Davey, Smith, Richard, Durbin, J., Brent Richard, Steve E., Humphrie, Eleftheria, Zeggini, Nicole, Soranzo, Saeed Al, Turki, Carl, Anderson, Richard, Anney, Dinu, Antony, Maria Soler, Artiga, Muhammad, Ayub, Senduran, Balasubramaniam, Jeffrey C., Barrett, Inês, Barroso, Phil, Beale, Jamie, Bentham, Shoumo, Bhattacharya, Ewan, Birney, Douglas, Blackwood, Martin, Bobrow, Elena, Bochukova, Patrick, Bolton, Rebecca, Bound, Chris, Boustred, Gerome, Breen, Mattia, Calissano, Keren, Car, Krishna, Chatterjee, Antonio, Ciampi, Sebhattin, Cirak, Peter, Clapham, Gail, Clement, Guy, Coate, David, Collier, Catherine, Cosgrove, Tony, Cox, Nick, Craddock, Lucy, Crook, Sarah, Curran, David, Curti, Allan, Daly, Aaron Day, William, Ian N. M., Day, Thomas, Down, Yuanping, Du, Ian, Dunham, Sarah, Edkin, Peter, Elli, David, Evan, Sadaf, Faroogi, Ghazaleh, Fatemifar, David R., Fitzpatrick, Paul, Flicek, James, Flyod, A., Reghan Foley, Christopher S., Franklin, Louise, Gallagher, Tom, Gaunt, Matthias, Geih, Daniel, Geschwind, Celia, Greenwood, Heather, Griffin, Detelina, Grozeva, Xueqin, Guo, Xiaosen, Guo, Hugh, Gurling, Deborah, Hart, Audrey, Hendrick, Peter, Holman, Bryan, Howie, Liren, Huang, Tim, Hubbard, Matthew E., Hurle, Pirro, Hysi, David K., Jackson, Yalda, Jamshidi, Tian, Jing, Chris, Joyce, Jane, Kaye, Thomas, Keane, Julia, Keogh, John, Kemp, Karen, Kennedy, Anja Kolb, Kokocinski, Genevieve, Lachance, Cordelia, Langford, Daniel, Lawson, Irene, Lee, Monkol, Lek, Jieqin, Liang, Hong, Lin, Rui, Li, Yingrui, Li, Ryan, Liu, Jouko, Lönnqvist, Margarida, Lope, Valentina, Lotchkova, Daniel, Macarthur, Jonathan, Marchini, John, Maslen, Mangino, Massimo, Iain, Mathieson, Gaëlle, Marenne, Peter, Mcguffin, Andrew, Mcintosh, Andrew G., Mckechanie, Andrew, Mcquillin, Sarah, Metrustry, Josine, Min, Hannah, Mitchison, Alireza, Moayyeri, James, Morri, Francesco, Muntoni, Kate, Northstone, Michael, O'Donnovan, Alexandros, Onoufriadi, Stephen, O'Rahilly, Karim, Oualkacha, Michael J., Owen, Aarno, Palotie, Kalliope, Panoutsopoulou, Victoria, Parker, Jeremy R., Parr, Lavinia, Paternoster, Tiina, Paunio, Felicity, Payne, John, Perry, Olli, Pietilainen, Vincent, Plagnol, Lydia, Quaye, Michael A., Quail, Lucy, Raymond, Karola, Rehnström, Brent, Richard, Susan, Ring, Graham R. S., Ritchie, Nicola, Robert, David B., Savage, Peter, Scambler, Stephen, Schiffel, Miriam, Schmidt, Nadia, Schoenmaker, Robert K., Semple, Eva, Serra, Sally I., Sharp, Hasheem, Shihab, David, Skuse, Kerrin, Small, Olivera Spasic, Boskovic, Tim, Spector, David St, Clair, Jim, Stalker, Elizabeth, Steven, Beate St, Pourcian, Jianping, Sun, Gabriela, Surdulescu, Jaana, Suvisaari, Ionna, Tachmazidou, Nicholas, Timpson, Martin D., Tobin, Ana, Valde, Margriet Van, Kogelenberg, Parthiban, Vijayarangakannan, Peter M., Visscher, Louise V., Wain, James T. R., Walter, Guangbiao, Wang, Jun, Wang, Yu, Wang, Kirsten, Ward, Elanor, Wheeler, Tamieka, Whyte, Hywel, William, Kathleen A., Williamson, Crispian, Wilson, Scott G., Wilson, Kim, Wong, Changjiang, Xu, Jian, Yang, Fend, Zhang, Pingbo, Zhang, and Hou Feng, Zheng

Subjects
Very low-density lipoprotein, Population, vldl, apoc3, General Physics and Astronomy, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, rare mutations, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, genome-wide association study (GWAS), plasma lipids, 0302 clinical medicine, Polymorphism (computer science), Genetic variation, Settore MED/14 - NEFROLOGIA, Allele, education, Allele frequency, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, cholesterol, General Chemistry, Minor allele frequency
Abstract

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale., Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3 gene strongly associated with plasma triglyceride levels.

Published
2014
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22. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

Author

Bernhard O. Boehm, Marten H. Hofker, Clara C. Elbers, Sam E. Tischfield, Yvonne T. van der Schouw, Richa Saxena, Caitrin W. McDonough, Kandice Kottke-Marchant, Folkert W. Asselbergs, Heribert Schunkert, L. Adrienne Cupples, Nicole L. Glazer, Philippa J. Talmud, John G. Gums, Wolfgang Koenig, Debbie A Lawlor, Matthew B. Lanktree, Myriam Fornage, Andrea Z. LaCroix, A. H. Zwinderman, Alice V. Stanton, Ronald P. Stolk, Kristian M. Bailey, Jeffery R. O'Connell, James S. Pankow, Jolanda M. A. Boer, Brendan J. Keating, Alan R. Shuldiner, Christian Hengstenberg, Yun Li, Olle Melander, Christian Delles, Gail P. Jarvik, John Whitfield, Stephen Newhouse, Rita P.S. Middelberg, Winfried März, Arthur A.M. Wilde, Patricia B. Munroe, Yan Gong, Herman A. Taylor, Denis C. Shields, Hugh Watkins, Ronald Klein, Charles Kooperberg, Hans L. Hillege, Elina Toskala, Christie M. Ballantyne, Mingyao Li, Suzanne Rafelt, Nilesh J. Samani, Bruce H. R. Wolffenbuttel, Kent R. Bailey, Pieter A. Doevendans, Yii-Der Ida Chen, Jens Baumert, Peter Sever, Vinicius Tragante, Florianne Bauer, Sonia S. Anand, W. M. Monique Verschuren, Braxton D. Mitchell, Barbara Thorand, Daniel I. Swerdlow, Jonathan A. Shaffer, Barbara E.K. Klein, Kiang Liu, Michael Y. Tsai, Neil R Poulter, Nicholas J. Schork, Simon P. R. Romaine, Bernhard M. Kaess, Mark J. Caulfield, Wei Chen, Erin N. Smith, Connie R. Bezzina, Stephen S. Rich, Tushar Bhangale, Leslie A. Lange, Mika Kivimäki, John Barnard, Julie A. Johnson, Roy L. Silverstein, Daichi Shimbo, Yiran Guo, Jessica van Setten, Meena Kumari, Berta Almoguera, Claire E. Hastie, Marcus E. Kleber, Robert A. Hegele, Mieke D. Trip, Matthijs F.L. Meijs, Bruce M. Psaty, Tina Shah, Susan Redline, Eric Boerwinkle, Cisca Wijmenga, Jonas S. Dejong, Catharina A. Hartman, Karen J. Cruickshanks, Taimour Y. Langaee, Amber A. Burt, Niek Verweij, David Duggan, Jerome I. Rotter, Ellen Van Der Schoot, Sathanur R. Srinivasan, N. Charlotte Onland-Moret, Paul Burton, Hakon Hakonarson, Laya Mallela, Fotios Drenos, Yolande Appelman, Rhonda M. Cooper-DeHoff, Peter S. Braund, Eric J. Topol, Michael V. Holmes, Grant W. Montgomery, Hubert Scharnagl, Alexander P. Reiner, Susan Kirkland, Daniel J. Rader, John C. Whittaker, Clement E. Furlong, Suthesh Sivapalaratnam, Gerald S. Berenson, Kiran Musunuru, Steve E. Humphries, Toby Johnson, Sarah S. Murray, Ramakrishnan Rajagopalan, Paul I.W. de Bakker, Erik P A Van Iperen, John J.P. Kastelein, Robert Clarke, Jemma C. Hopewell, Thomas Illig, Wendy S. Post, Anna F. Dominiczak, Christopher P. Nelson, Amber L. Beitelshees, Gurunathan Murugesan, Pim van der Harst, G. Kees Hovingh, Muredach P. Reilly, Karina W. Davidson, John M. C. Connell, Anthony J. Balmforth, James G. Wilson, Jose M. Ordovas, Sarah G. Buxbaum, Tom R. Gaunt, Jana V. van Vliet-Ostaptchouk, Li Zhang, Peter J. van der Most, Ian N. M. Day, Willem H. Ouwehand, Salim Yusuf, Haiqing Shen, Sekar Kathiresan, Nathan Pankratz, Sandosh Padmanabhan, Pamela J. Schreiner, Alistair S. Hall, Juan P. Casas, Nicholas G. Martin, Joost L. Van Pelt, Kelly A. Volcik, Aroon D. Hingorani, Cardiology, ICaR - Heartfailure and pulmonary arterial hypertension, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Landsteiner Laboratory, and Clinical Haematology

Subjects
Male, Candidate gene, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Medical and Health Sciences, 0302 clinical medicine, APOLIPOPROTEIN B-100, Missing heritability problem, MISSING HERITABILITY, 2.1 Biological and endogenous factors, Genetics(clinical), Aetiology, FAMILIAL HYPERCHOLESTEROLEMIA, Genetics (clinical), Genetics, Genetics & Heredity, 0303 health sciences, QUANTITATIVE TRAITS, Single Nucleotide, Biological Sciences, Lipids, 3. Good health, SNP genotyping, PLASMA TRIGLYCERIDES, Cholesterol, Phenotype, DENSITY-LIPOPROTEIN CHOLESTEROL, lipids (amino acids, peptides, and proteins), Female, HDL, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, STATISTICAL-MODEL, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, LDL, 03 medical and health sciences, Sex Factors, Humans, CORONARY-HEART-DISEASE, Polymorphism, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, 030304 developmental biology, Genetic association, COMPLEX TRAITS, Human Genome, Cholesterol, HDL, nutritional and metabolic diseases, Cholesterol, LDL, Atherosclerosis, LifeLines Cohort Study, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. © 2012 The American Society of Human Genetics.

Published
2016
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23. Marginal role for 53 common genetic variants in cardiovascular disease prediction

Author

Fotios Drenos, Mika Kivimäki, Philippa J. Talmud, Jorgen Engmann, Steve E. Humphries, Caroline Dale, Meena Kumari, Peter H. Whincup, Juan P. Casas, Frank Dudbridge, Diana Kuh, Andrew Wong, Yoav Ben-Shlomo, Stela McLachlan, Richard W Morris, Rebecca Hardy, S. Goya Wannamethee, Aroon D. Hingorani, Barbara J. Jefferis, Tina Shah, Jacqueline F. Price, and Jackie A. Cooper

Subjects
0301 basic medicine, Adult, Genetic Markers, Male, medicine.medical_specialty, Time Factors, Single-nucleotide polymorphism, Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Humans, False Positive Reactions, Genetic Predisposition to Disease, Prospective Studies, Prospective cohort study, Genetic Association Studies, Framingham Risk Score, Receiver operating characteristic, business.industry, Gene Expression Profiling, Incidence, Reproducibility of Results, Middle Aged, United Kingdom, 3. Good health, 030104 developmental biology, Phenotype, ROC Curve, Genetic marker, Cardiovascular Diseases, Predictive value of tests, Area Under Curve, Female, Cardiology and Cardiovascular Medicine, Risk assessment, business
Abstract

Objective: We investigated discrimination and calibration of cardiovascular disease (CVD) risk scores when genotypic was added to phenotypic information. The potential of genetic information for those at intermediate risk by a phenotype-based risk score was assessed. Methods: Data were from seven prospective studies including 11,851 individuals initially free of CVD or diabetes, with 1,444 incident CVD events over 10 years’ follow-up. We calculated a score from 53 CVD-related single nucleotide polymorphisms (SNPs) and an established CVD risk equation “QRISK-2” comprising phenotypic measures. The area under the receiver operating characteristic curve (AUROC), detection rate for given false positive rate (FPR), and net reclassification index (NRI) were estimated for gene scores alone and in addition to the QRISK-2 CVD risk score. We also evaluated use of genetic information only for those at intermediate risk according to QRISK-2. Results: The AUROC was 0.635 for QRISK-2 alone, and 0.623 with addition of the gene score. The detection rate for 5% FPR improved from 11.9% to 12.0% when adding the gene score. For a 10-year CVD risk cut-off point of 10%, the NRI was 0.25% when the gene score was added to QRISK-2. Applying the genetic risk score only to those with QRISK-2 risk of 10-Conclusions: The gene score produced minimal incremental population-wide utility over phenotypic risk prediction of CVD. Tailored prediction using genetic information for those at intermediate risk may have clinical utility.

Published
2016
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24. The Gene Ontology: enhancements for 2011

Author

P D'Eustachio, Benjamin C. Hitz, Julie Park, Paul Browne, Douglas G. Howe, Cynthia J. Krieger, Kalpana Karra, Stan Laulederkind, Karen R. Christie, Susan Tweedie, Eurie L. Hong, Lydie Bougueleret, Michele Magrane, Cathy R. Gresham, Rolf Apweiler, Lisa Matthews, Dong Li, Philippa J. Talmud, Ioannis Xenarios, J. M. Cherry, Tanya Z. Berardini, Deborah A. Siegele, Rama Balakrishnan, D. Sitnikov, A. Auchinchloss, Selina S. Dwight, Tony Sawford, Paul J. Kersey, Ruth C. Lovering, Ruth Y. Eberhardt, Ursula Hinz, Lakshmi Pillai, Sylvain Poux, Edith D. Wong, Klemens Pichler, Kati Laiho, Malcolm J. Gardner, Stephen G. Oliver, Lionel Breuza, Kara Dolinski, P Lemercier, Kristian B. Axelsen, Midori A. Harris, Adrienne E. Zweifel, H. Drabkin, Guillaume Keller, Marek S. Skrzypek, Daniel M. Staines, Fiona M. McCarthy, Nicholas H. Brown, Mark D. McDowall, Antonia Lock, Mary Shimoyama, Maria C. Costanzo, Teresia Buza, S. Jimenez, Rex L. Chisholm, Paul W. Sternberg, Hui Wang, Nadine Gruaz-Gumowski, Chantal Hulo, Rebecca E. Foulger, Melinda R. Dwinell, Judith A. Blake, Marcus C. Chibucos, B. K. McIntosh, C. D. Amundsen, Jane Lomax, L Famiglietti, Tom Hayman, Michael Tognolli, Eva Huala, James C. Hu, Patrick Masson, Maria Jesus Martin, Benoit Bely, Shuai Weng, Heather C. Wick, E. Dimmer, L. Ni, Catherine Rivoire, Christopher J. Mungall, H. Sehra, P. Duek-Roggli, Maria Victoria Schneider, Dianna G. Fisk, Michael S. Livstone, Ivo Pedruzzi, Shyamala Sundaram, Donna K. Slonim, Isabelle Cusin, Stuart R. Miyasato, Timothy F. Lowry, Varsha K. Khodiyar, Seth Carbon, Elisabeth Coudert, Jürg Bähler, Juancarlos Chan, Evelyn Camon, Daniel P. Renfro, Anne Estreicher, M. C. Blatter, Robert S. Nash, P Gaudet, Sven Heinicke, K. Van Auken, Stacia R. Engel, Alan Bridge, Ralf Stephan, Mary E. Dolan, Shane C. Burgess, Petra Fey, Shur-Jen Wang, Damien Lieberherr, Duncan Legge, P. Porras Millán, Andre Stutz, Yasmin Alam-Faruque, Gail Binkley, Bernd Roechert, S. Branconi-Quintaje, Ghislaine Argoud-Puy, S. Basu, Kim Rutherford, M. Moinat, Monte Westerfield, Arnaud Gos, Eleanor J Stanley, Valerie Wood, Ranjana Kishore, Diego Poggioli, S. Ferro-Rojas, Victoria Petri, Florence Jungo, Suzanna E. Lewis, Emmanuel Boutet, Warren A. Kibbe, M Feuermann, Claire O'Donovan, W. M. Chan, J. James, David P. Hill, Rachael P. Huntley, M. Gwinn Giglio, Paul Thomas, Jodi E. Hirschman, Paola Roncaglia, Gene Ontology Consortium, Blake, JA., Dolan, M., Drabkin, H., Hill, DP., Ni, L., Sitnikov, D., Burgess, S., Buza, T., Gresham, C., McCarthy, F., Pillai, L., Wang, H., Carbon, S., Lewis, SE., Mungall, CJ., Gaudet, P., Chisholm, RL., Fey, P., Kibbe, WA., Basu, S., Siegele, DA., McIntosh, BK., Renfro, DP., Zweifel, AE., Hu, JC., Brown, NH., Tweedie, S., Alam-Faruque, Y., Apweiler, R., Auchinchloss, A., Axelsen, K., Argoud-Puy, G., Bely, B., Blatter, M-., Bougueleret, L., Boutet, E., Branconi, S., Breuza, L., Bridge, A., Browne, P., Chan, WM., Coudert, E., Cusin, I., Dimmer, E., Duek-Roggli, P., Eberhardt, R., Estreicher, A., Famiglietti, L., Ferro-Rojas, S., Feuermann, M., Gardner, M., Gos, A., Gruaz-Gumowski, N., Hinz, U., Hulo, C., Huntley, R., James, J., Jimenez, S., Jungo, F., Keller, G., Laiho, K., Legge, D., Lemercier, P., Lieberherr, D., Magrane, M., Martin, MJ., Masson, P., Moinat, M., O'Donovan, C., Pedruzzi, I., Pichler, K., Poggioli, D., Porras Millán, P., Poux, S., Rivoire, C., Roechert, B., Sawford, T., Schneider, M., Sehra, H., Stanley, E., Stutz, A., Sundaram, S., Tognolli, M., Xenarios, I., Foulger, R., Lomax, J., Roncaglia, P., Camon, E., Khodiyar, VK., Lovering, RC., Talmud, PJ., Chibucos, M., Gwinn Giglio, M., Dolinski, K., Heinicke, S., Livstone, MS., Stephan, R., Harris, MA., Oliver, SG., Rutherford, K., Wood, V., Bahler, J., Lock, A., Kersey, PJ., McDowall, MD., Staines, DM., Dwinell, M., Shimoyama, M., Laulederkind, S., Hayman, T., Wang, S-., Petri, V., Lowry, T., D'Eustachio, P., Matthews, L., Amundsen, CD., Balakrishnan, R., Binkley, G., Cherry, JM., Christie, KR., Costanzo, MC., Dwight, SS., Engel, SR., Fisk, DG., Hirschman, JE., Hitz, BC., Hong, EL., Karra, K., Krieger, CJ., Miyasato, SR., Nash, RS., Park, J., Skrzypek, MS., Weng, S., Wong, ED., Berardini, TZ., Li, D., Huala, E., Slonim, D., Wick, H., Thomas, P., Chan, J., Kishore, R., Sternberg, P., Van Auken, K., Howe, D., and Westerfield, M.

Subjects
Quality Control, 0303 health sciences, media_common.quotation_subject, Databases, Genetic, Molecular Sequence Annotation/standards, Vocabulary, Controlled, Inference, Molecular Sequence Annotation, Articles, Biology, Ontology (information science), World Wide Web, Open Biomedical Ontologies, 03 medical and health sciences, Annotation, 0302 clinical medicine, Resource (project management), Controlled vocabulary, Genetics, Social media, Function (engineering), 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract

The Gene Ontology (GO) (http://www.geneontology.org) is a community bioinformatics resource that represents gene product function through the use of structured, controlled vocabularies. The number of GO annotations of gene products has increased due to curation efforts among GO Consortium (GOC) groups, including focused literature-based annotation and ortholog-based functional inference. The GO ontologies continue to expand and improve as a result of targeted ontology development, including the introduction of computable logical definitions and development of new tools for the streamlined addition of terms to the ontology. The GOC continues to support its user community through the use of e-mail lists, social media and web-based resources.

Published
2011
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25. Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study

Author

S. Matthijs Boekholdt, John J.P. Kastelein, Alain Tedgui, Kay-Tee Khaw, Amir Ravandi, Philippa J. Talmud, Sotirios Tsimikas, Joseph L. Witztum, Elizabeth R. Miller, Nicholas J. Wareham, Ziad Mallat, Joelle Benessiano, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine

Subjects
Male, medicine.medical_specialty, Apolipoprotein B, oxidation, Antigen-Antibody Complex, QD415-436, Biochemistry, Coronary artery disease, chemistry.chemical_compound, Endocrinology, Risk Factors, Diabetes mellitus, Internal medicine, antibody, medicine, Humans, Aged, Autoantibodies, Inflammation, Framingham Risk Score, biology, business.industry, Autoantibody, Cell Biology, Middle Aged, medicine.disease, Malondialdehyde, Lipoproteins, LDL, Immunoglobulin M, chemistry, Cardiovascular Diseases, Case-Control Studies, Immunoglobulin G, biology.protein, Female, lipids (amino acids, peptides, and proteins), Metabolic syndrome, atherosclerosis, Patient-Oriented and Epidemiological Research, business, low density lipoprotein, Oxidation-Reduction, Biomarkers, Lipoprotein
Abstract

Levels of IgG and IgM autoantibodies (AA) to malondialdehyde (MDA)-LDL and apoB-immune complexes (ICs) were measured in 748 cases and 1,723 controls in the EPIC-Norfolk cohort and their association to coronary artery disease (CAD) events determined. We evaluated whether AA and IC modify CAD risk associated with secretory phospholipase A(2) (sPLA(2)) type IIA mass and activity, lipoprotein-associated PLA(2) activity, lipoprotein (a) [Lp(a)], oxidized phospholipids on apoB-100 (OxPL/apoB), myeloperoxidase, and high sensitivity C-reactive protein. IgG ICs were higher in cases versus controls (P = 0.02). Elevated levels of IgM AA and IC were inversely associated with Framingham Risk Score and number of metabolic syndrome criteria (p range 0.02-0.001). In regression analyses adjusted for age, smoking, diabetes, LDL-cholesterol, HDL-cholesterol, and systolic blood pressure, the highest tertiles of IgG and IgM AA and IC were not associated with higher risk of CAD events compared with the lowest tertiles. However, elevated levels of IgM IC reduced the risk of Lp(a) (P = 0.006) and elevated IgG MDA-LDL potentiated the risk of sPLA(2) mass (P = 0.018). This epidemiological cohort of initially healthy subjects shows that IgG and IgM AA and IC are not independent predictors of CAD events but may modify CAD risk associated with elevated levels of oxidative biomarkers.

Published
2011

26. Genetic Variants Associated with von Willebrand Factor Levels in Healthy Men and Women Identified Using the HumanCVD BeadChip

Author

Michael Marmot, Gordon D.O. Lowe, Elina Hyppönen, Reecha Sofat, Delilah Zabaneh, Jutta Palmen, Santiago Rodriguez, Juan P. Casas, John C. Whittaker, Richard W Morris, Meena Kumari, Mika Kivimäki, Tom R. Gaunt, Diane J. Berry, George Davey Smith, Peter H. Whincup, Sonia Shah, Ann Rumley, Ian N. M. Day, Chris Power, Philippa J. Talmud, Steve E. Humphries, Fotios Drenos, Aroon D. Hingorani, Tina Shah, Debbie A Lawlor, Jacky Pallas, and Shah Ebrahim

Subjects
Genetics, congenital, hereditary, and neonatal diseases and abnormalities, biology, Genetic variants, Locus (genetics), Single-nucleotide polymorphism, Von Willebrand factor, hemic and lymphatic diseases, ABO blood group system, Genotype, biology.protein, SNP, Allele, Genetics (clinical), circulatory and respiratory physiology
Abstract

We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.

Published
2011
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27. Lipoprotein association studies: taking stock and moving forward

Author

Nikos Yiannakouris, Philippa J. Talmud, and Steve E. Humphries

Subjects
Genetics, Nutrition and Dietetics, Lipoproteins, Endocrinology, Diabetes and Metabolism, Genetic Variation, Genome-wide association study, Lipid metabolism, Cell Biology, Biology, Explained variation, Polymorphism, Single Nucleotide, Databases as Topic, Cardiovascular Diseases, Humans, SNP, Cardiology and Cardiovascular Medicine, Molecular Biology, Gene, Exome sequencing, Imputation (genetics), Genome-Wide Association Study, Genetic association
Abstract

Purpose of reviewOver the last year, huge progress has been made using SNP arrays to identify genes associated with lipid traits.Recent findingsThe single genome-wide association studies (GWASs) may have reached a limit in identifying novel genes, but there has been tremendous progress from collaborative consortia examining pooled data from GWASs, often employing SNP imputation. For example, the Global Lipid Consortium reported that 56 of the 95 lipid-associated loci were novel to the pooled analysis from over 100 000 individuals. Complementary to this, a gene-centric approach, such as the 50K IBC HumanCVD chip, which provides deep coverage of approximately 2100 genes, has had success in ascertaining independently acting variants and helped us to move a step closer to identify functional variants. Yet irrespective of the platform used, for each trait, the percentage variance explained by these genes remains in the order of approximately 10-12% and it is still unclear to what extent rare mutations, identified by resequencing or exome sequencing approaches, or gene x gene and gene x environment studies, might boost this.SummaryGWAS-identified novel lipid-related loci highlight new pathways in lipid metabolism and may provide innovative drug targets. Furthermore, the use of lipid gene scores, over and above a single lipid measure, may have clinical utility.

Published
2011
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28. SERPINA1 11478G->A variant, serum 1-antitrypsin, exacerbation frequency and FEV1 decline in COPD

Author

Philippa J. Talmud, Meena Kumari, Gavin C. Donaldson, Jennifer K Quint, and John R. Hurst

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Genotype, Exacerbation, Gastroenterology, Pulmonary Disease, Chronic Obstructive, Gene Frequency, Polymorphism (computer science), Forced Expiratory Volume, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Allele frequency, COPD, Polymorphism, Genetic, Interleukin-6, business.industry, Respiratory disease, Case-control study, Middle Aged, medicine.disease, respiratory tract diseases, Genotype frequency, C-Reactive Protein, Case-Control Studies, alpha 1-Antitrypsin, Immunology, Disease Progression, Female, business, Biomarkers
Abstract

Background The α 1 -antitrypsin 11478G→A polymorphism may be associated with attenuated acute α 1 -antitrypsin responses. It was hypothesised that patients with chronic obstructive pulmonary disease (COPD) and this mutation have accelerated lung function decline. Objective To assess whether the 11478G→A polymorphism is associated with attenuated α 1 -antitrypsin responses at COPD exacerbation, and therefore accelerated lung function decline. Methods Lung function decline by genotype was examined in the English Longitudinal Study of Ageing (ELSA; n=1805) and Whitehall II (n=2733) studies. 204 patients with COPD were genotyped in the London cohort and serum α 1 -antitrypsin concentration was measured at baseline and (n=92) exacerbation. Results The 11478G→A genotype frequencies did not vary between COPD cases and controls, or between COPD frequent and infrequent exacerbators. Subjects with the rare A allele experienced more rapid lung function decline in the Whitehall II (A vs non-A: 16 vs 4 ml/year p=0.02) but not ELSA (29 vs 34 ml/year, p=0.46) or London cohorts (26 vs 38 ml/year, p=0.06). Decline was not greater in frequent exacerbator A versus non-A carriers (20 vs 24 ml/year, p=0.58). Upregulation of α 1 -antitrypsin at exacerbation was not demonstrated, even in patients homozygous for the common allele (median exacerbation change −0.07 g/l 11478GG, p=0.87 and −0.09 g/l 11478AA/GA, p=0.92; p=0.90 for difference). In patients with the A allele, there was no correlation between serum α 1 -antitrypsin and serum interleukin 6 (IL-6) concentrations. Conclusion The 11478G→A α 1 -antitrypsin polymorphism is not associated with increased risk of developing COPD, nor accelerated lung function decline. Serum α 1 -antitrypsin may not be upregulated early at COPD exacerbation. In patients with the 11478G→A polymorphism there was no relationship between the serum α 1 -antitrypsin and serum IL-6 concentrations.

Published
2011
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29. Genetic variation in complement factor H and risk of coronary heart disease: Eight new studies and a meta-analysis of around 48,000 individuals

Author

Alun D. Hughes, Aroon D. Hingorani, Shah Ebrahim, Philippa J. Talmud, Steve E. Humphries, Debbie A Lawlor, Meena Kumari, Reecha Sofat, Liam Smeeth, Simon Thom, Mika Kivimäki, Michael Marmot, John C. Whittaker, Helen Ireland, and Juan P. Casas

Subjects
Male, Risk, medicine.medical_specialty, Genotype, Myocardial Infarction, Coronary Disease, Genome-wide association study, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Risk factor, Triglycerides, 030304 developmental biology, Genetic association, 2. Zero hunger, Genetics, Molecular Epidemiology, 0303 health sciences, C-reactive protein, Genetic Variation, Sequence Analysis, DNA, Odds ratio, eye diseases, 3. Good health, Genetic epidemiology, Complement Factor H, Factor H, biology.protein, Female, Cardiology and Cardiovascular Medicine
Abstract

OBJECTIVES: To investigate the association of polymorphisms in complement factor H (CFH) and coronary heart disease (CHD) using meta-analysis. BACKGROUND: Age-related macular degeneration (AMD) and CHD may share partially overlapping pathogenesis. A non-synonymous SNP (rs1061170/Y402H) in CFH encoding complement factor H (fH) is robustly associated with increased AMD risk but associations with CHD risk have been inconsistent. METHODS: We conducted de novo genotyping and genetic association analyses of incident and prevalent CHD in four studies, and in silico analysis of the same association in a further four cohorts. We pooled these data with information from all published studies using random effects meta-analysis, including a total of 48,646 participants of which 9097 were CHD cases. We also evaluated the association of Y402H with known risk factors for CHD by pooling results from new and in silico studies providing relevant data. RESULTS: CFH genotype was not associated with CHD. Compared to the reference TT homozygote group the pooled odds ratio (OR) for individuals homozygous for the C allele was 1.02, 95% CI (0.91, 1.13) and that for heterozygote TC individuals was 1.04 (0.98, 1.10). There was no association of CFH with systolic and diastolic blood pressure, total-, LDL- and HDL-cholesterol, or body mass index. Individuals who were CC compared to TT had higher triglyceride levels: pooled mean difference 0.06 (0.02, 0.10) mmol/L, p=0.005. CONCLUSIONS: The AMD-associated CFH genotype is not associated with CHD. With the possible exception of triglycerides, this CFH SNP was not associated with a wide range of other CHD risk factors.

Published
2010
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30. The Relationship Between Plasma Angiopoietin-like Protein 4 Levels, Angiopoietin-like Protein 4 Genotype, and Coronary Heart Disease Risk

Author

S. Matthijs Boekholdt, Marius R. Robciuc, Meena Kumari, Alistair S. Hall, Nilesh J. Samani, Matti Jauhiainen, Jackie A. Cooper, Nicholas J. Wareham, Tom R. Gaunt, Melissa C. Smart-Halajko, Ian N.M. Day, Philippa J. Talmud, Steve E. Humphries, Christopher P. Nelson, Christian Ehnholm, Mika Kivimäki, Peter S. Braund, Kay-Tee Khaw, Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
Male, medicine.medical_specialty, Genotype, Single-nucleotide polymorphism, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Article, Cell Line, Coronary artery disease, Risk Factors, ANGPTL4, Polymorphism (computer science), Internal medicine, medicine, Angiopoietin-Like Protein 4, Humans, Risk factor, Kidney, Vascular disease, Middle Aged, medicine.disease, Endocrinology, medicine.anatomical_structure, Cohort, Cardiology and Cardiovascular Medicine, Angiopoietins, Biomarkers
Abstract

Objective— To investigate the relationship between angiopoietin-like protein 4 (Angptl4) levels, coronary heart disease (CHD) biomarkers, and ANGPTL4 variants. Methods and Results— Plasma Angptl4 was quantified in 666 subjects of the Northwick Park Heart Study II using a validated ELISA. Seven ANGPTL4 single-nucleotide polymorphisms were genotyped, and CHD biomarkers were assessed in the whole cohort (N=2775). Weighted mean±SD plasma Angptl4 levels were 10.0±11.0 ng/mL. Plasma Angptl4 concentration correlated positively with age ( r =0.15, P r =0.19, P =0.003) but negatively with plasma high-density lipoprotein cholesterol ( r =−0.13, P =0.01). No correlation with triglycerides (TGs) was observed. T266M was independently associated with plasma Angptl4 levels ( P Conclusion— Circulating Angptl4 levels may not influence TG levels or CHD risk for the following reasons: (1) Angptl4 levels were not correlated with TGs; (2) T266M, although associated with Angptl4 levels, showed no association with plasma TGs; and (3) TG-lowering E40K did not influence Angptl4 levels. These results provide new insights into the role of Angptl4 in TG metabolism.

Published
2010
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31. Application of statistical and functional methodologies for the investigation of genetic determinants of coronary heart disease biomarkers: lipoprotein lipase genotype and plasma triglycerides as an exemplar

Author

Wendy Putt, Jutta Palmen, Andrew J. Smith, Fotios Drenos, Philippa J. Talmud, and Steve E. Humphries

Subjects
Male, Genotype, Gene Expression, Single-nucleotide polymorphism, Genome-wide association study, Coronary Disease, Electrophoretic Mobility Shift Assay, Biology, Polymorphism, Single Nucleotide, Genes, Reporter, Risk Factors, Genetics, SNP, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Triglycerides, Genetic association, Homeodomain Proteins, Lipoprotein lipase, Models, Statistical, Haplotype, Nuclear Proteins, General Medicine, Articles, Middle Aged, CREB-Binding Protein, SNP genotyping, Repressor Proteins, Lipoprotein Lipase, Hepatocyte Nuclear Factor 3-beta, Biomarkers, Genome-Wide Association Study, Transcription Factors
Abstract

Genome-wide association studies have proved very successful in identifying novel single-nucleotide polymorphisms (SNPs) associated with disease or traits, but the related, functional SNP is usually unknown. In this paper, we describe a methodology to locate and validate candidate functional SNPs using lipoprotein lipase (LPL), a gene previously associated with triglyceride levels, as an exemplar. Two thousand seven hundred and eighty-six healthy middle-aged men from the NPHSII UK prospective study (with up to six measures of plasma lipid levels) were genotyped for 20 LPL tagging (t)SNPs using Illumina Bead technology. Using model-selection procedures and haplotypes, we identified eight SNPs that consistently maximized the fit of the model to the phenotype. Fifteen SNPs in high linkage disequilibrium with these were identified, and functional assays were carried out on all 23 SNPs. Electrophoretic mobility shift assay (EMSA) was used to identify SNPs that had the potential to alter DNA-protein interactions, reducing the number to eight possible candidate SNPs. These were examined for ability to alter expression using a luciferase reporter assay, and two regulatory SNPs, showing genotype differences, rs327 and rs3289, were identified. Finally, multiplexed-competitor-EMSA (MC-EMSA) and supershift EMSA identified FOXA2 to rs327T, and CREB-binding protein (CBP) and CCAAT displacement protein (CDP) to rs3289C as the factors responsible for transcription binding. We have identified two novel candidate functional SNPs in LPL and presented a procedure aimed to efficiently detect SNPs potentially causal to genetic association. We believe that this methodology could be successfully applied to future re-sequencing data.

Published
2010

32. APOE/C1/C4/C2 Gene Cluster Genotypes, Haplotypes and Lipid Levels in Prospective Coronary Heart Disease Risk Among UK Healthy Men

Author

Gie Ken-Dror, Philippa J. Talmud, Steve E. Humphries, and Fotios Drenos

Subjects
Male, Apolipoprotein E, Linkage disequilibrium, medicine.medical_specialty, Apolipoprotein B, Coronary Disease, Single-nucleotide polymorphism, Lower risk, Bioinformatics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Apolipoproteins E, Gene Frequency, Risk Factors, Internal medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, Prospective Studies, Apolipoproteins C, Molecular Biology, Genetics (clinical), Proportional Hazards Models, Apolipoprotein C-I, biology, Haplotype, Hazard ratio, Middle Aged, United Kingdom, Apolipoproteins, Endocrinology, Haplotypes, Health, Multigene Family, biology.protein, Regression Analysis, Molecular Medicine, Apolipoprotein C-II, lipids (amino acids, peptides, and proteins), Research Article
Abstract

The role of common APOE variants on plasma lipids, particularly low density lipoprotein (LDL) levels, and coronary heart disease (CHD) risk is well known; the influence of variation in the other nearby apolipoprotein genes APOC1, APOC4 and APOC2 is unclear. This study examines the association between APOE/C1/C4/C2 gene cluster variation using tagging SNPs and plasma lipid concentration along with risk of CHD in a prospective cohort. Genotypes for 11 common APOE/C1/C4/C2 SNPs were determined in 2,767 middle-aged (49 to 64 years) men from the Second Northwick Park Heart Study, with 275 CHD events over a 15-year follow-up period. Seven SNPs showed significant associations with one or more lipid trait in univariate analysis. Multivariate and haplotype analysis showed that the APOE genotypes are most strongly associated with effects on LDL-C and apoB concentration (explaining 3.4% of the LDL-C variance) while the other SNPs in this gene cluster explained an additional 1.2%. Haplotypes in APOC2 and APOC4 were associated with modest effects on HDL-C and apoAI (explaining respectively 1.4% and 1.2%). Carriers of the APOE ɛ2 SNP had a significantly lower risk of CHD hazard ratio (HR) of 0.63 (95% confidence interval [CI]: 0.42–0.95), as did carriers of the APOC2 SNP rs5127 (HR = 0.72, 95% CI: 0.56–0.93), while carriers of APOC1 SNP rs4803770 had higher risk of CHD (HR = 1.36, 95% CI: 1.04–1.78) compared with noncarriers. While the common APOE polymorphism explains the majority of the locus genetic determinants of plasma lipid levels, additional SNPs in the APOC1/C2 region may contribute to CHD risk, but these effects require confirmation.

Published
2010
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33. Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms

Author

Jill T. Norman, Rachel J. Middleton, Ben Caplin, Philippa J. Talmud, Dorothea Nitsch, Douglas MacKenzie, David C. Wheeler, PS Veitch, Scott Blackwell, Richard Hoefield, Jackie A. Cooper, Herpreet Gill, and James Leiper

Subjects
Nephrology, Male, progression of chronic renal failure, medicine.medical_specialty, Methylarginine, Candidate gene, Genotype, Renal function, Arginine, Amidohydrolases, Cohort Studies, chemistry.chemical_compound, Gene Frequency, nitric oxide, Internal medicine, medicine, Humans, Longitudinal Studies, RNA, Messenger, Enzyme Inhibitors, Alleles, Kidney, Polymorphism, Genetic, business.industry, Case-control study, Genetic Variation, medicine.disease, medicine.anatomical_structure, Endocrinology, Cross-Sectional Studies, chemistry, Case-Control Studies, Kidney Failure, Chronic, Female, Asymmetric dimethylarginine, business, polymorphisms, Kidney disease, Glomerular Filtration Rate
Abstract

In patients with chronic kidney disease, high plasma levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, are thought to contribute to decline in renal function. Here we took a candidate gene approach to determine any causal role of asymmetric dimethylarginine in the progression of chronic kidney disease. The impact of single-nucleotide polymorphisms in the genes encoding the two isoforms of the asymmetric dimethylarginine-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), on enzyme expression, plasma asymmetric dimethylarginine levels, and longitudinal changes in estimated glomerular filtration rate were determined in various patient groups. There was evidence suggesting that the rs17384213 DDAH1 GG genotype was associated with increased expression of its mRNA in kidney allografts. Healthy subjects carrying the rs17384213 G allele had lower plasma asymmetric dimethylarginine, and a similar borderline association was found in patients with chronic kidney disease. This allele, however, was independently associated with a steeper decline in renal function in two separate cohorts of patients with chronic kidney disease. We conclude that polymorphisms in DDAH1 alter the rate of decline of glomerular filtration rate in subjects with chronic kidney disease. Our findings show that DDAH1 modulates plasma asymmetric dimethylarginine and contributes to the decline in renal function. However, it appears that increases in circulating methylarginine did not mediate progressive kidney injury.

Published
2010
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34. Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

Author

Marcello Arca, François Cambien, Wiek H. van Gilst, Robin P. F. Dullaart, Michael J. Pencina, Shinji Yokoyama, Folkert W. Asselbergs, S. Matthijs Boekholdt, John F. Thompson, Aaron Isaacs, Jacqueline C.M. Witteman, Odette Poirer, Gerjan Navis, Pamela A. McCaskie, John E. Deanfield, Ian Ford, Aroon D. Hingorani, Viviane Nicaud, Carlo Gaudio, Nicholas J. Wareham, Bernhard Paulweber, Kay-Tee Khaw, Meena Kumari, Dirk J. van Veldhuisen, Lyle J. Palmer, Naveed Sattar, Ramachandran S. Vasan, José V. Sorlí, Jose M. Ordovas, Sally L. Ricketts, Heikki Kauma, Benjamin D. Horne, Mika Kivimäki, Philippa J. Talmud, Fabiana Quagliarini, Juan P. Casas, Steve E. Humphries, Tina Shah, Reecha Sofat, Shah Ebrahim, A. Sandhofer, John J.P. Kastelein, Dilys J. Freeman, Kenji Okumura, Jackie A. Cooper, Debbie A Lawlor, Tricia Li, Liam Smeeth, Cornelia M. van Duijn, Chris J. Packard, Akimoto Goto, Sakari Kakko, Pim van der Harst, Manjinder S. Sandhu, Ralph B. D'Agostino, Michael Marmot, Y. Antero Kesäniemi, Vilmundur Gudnason, Valerie McCormack, Markku J. Savolainen, George Davey Smith, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, and Epidemiology

Subjects
high-density lipoproteins, Epidemiology, BLOOD-PRESSURE, Pharmacology, DISEASE, chemistry.chemical_compound, DOUBLE-BLIND, High-density lipoprotein, CIENCIAS MÉDICAS ::Medicina interna [UNESCO], Polymorphism (computer science), Physiology (medical), Cholesterylester transfer protein, Genetics, Medicine, genetics, High-density lipoproteins, GENOME-WIDE ASSOCIATION, UNESCO::CIENCIAS MÉDICAS ::Medicina interna, HDL CHOLESTEROL, biology, business.industry, Cholesterol, Torcetrapib, CIENCIAS MÉDICAS [UNESCO], Dose–response relationship, Blood pressure, chemistry, ATHEROSCLEROSIS, UNESCO::CIENCIAS MÉDICAS, biology.protein, MENDELIAN RANDOMIZATION, epidemiology, pharmacology, lipids (amino acids, peptides, and proteins), TORCETRAPIB, Cardiology and Cardiovascular Medicine, business, HIGH-DENSITY-LIPOPROTEIN, LIPID-LEVELS, Lipoprotein
Abstract

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI −0.28 to 0.60 mm Hg) and diastolic blood pressure (−0.04 mm Hg, 95% CI −0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Published
2010

35. Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip

Author

Philippa J, Talmud, Fotios, Drenos, Sonia, Shah, Tina, Shah, Jutta, Palmen, Claudio, Verzilli, Tom R, Gaunt, Jacky, Pallas, Ruth, Lovering, Kawah, Li, Juan Pablo, Casas, Reecha, Sofat, Meena, Kumari, Santiago, Rodriguez, Toby, Johnson, Stephen J, Newhouse, Anna, Dominiczak, Nilesh J, Samani, Mark, Caulfield, Peter, Sever, Alice, Stanton, Denis C, Shields, Sandosh, Padmanabhan, Olle, Melander, Claire, Hastie, Christian, Delles, Shah, Ebrahim, Michael G, Marmot, George Davey, Smith, Debbie A, Lawlor, Patricia B, Munroe, Ian N, Day, Mika, Kivimaki, John, Whittaker, Steve E, Humphries, Aroon D, Hingorani, and Sverre, Kjeldsen

Subjects
Adult, Male, Apolipoprotein B, Population, Blood lipids, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Apolipoproteins A, Polymorphism, Single Nucleotide, White People, Article, Apolipoproteins E, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, Humans, Computer Simulation, Genetics(clinical), education, Genetics (clinical), Alleles, Triglycerides, 030304 developmental biology, Apolipoproteins B, Probability, 0303 health sciences, education.field_of_study, biology, Apolipoprotein A-I, Cholesterol, HDL, Genetic Variation, Lipid metabolism, Cholesterol, LDL, Middle Aged, Lipids, 3. Good health, Apolipoproteins, Apolipoprotein A-V, Cardiovascular Diseases, biology.protein, lipids (amino acids, peptides, and proteins), Female
Abstract

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p < 10−5, with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p < 10−4 in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n > 12,500) revealed previously unreported associations of SH2B3 (p < 2.2 × 10−6), BMPR2 (p < 2.3 × 10−7), BCL3/PVRL2 (flanking APOE; p < 4.4 × 10−8), and SMARCA4 (flanking LDLR; p < 2.5 × 10−7) with LDL cholesterol. Common alleles in these genes explained 6.1%–14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [∼1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.

Published
2009
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36. C-Reactive Protein and Coronary Heart Disease: Predictive Test or Therapeutic Target?

Author

Tina Shah, Juan P. Casas, Philippa J. Talmud, Steve E. Humphries, and Aroon D. Hingorani

Subjects
Clinical Biochemistry, Coronary Disease, Disease, Bioinformatics, law.invention, Randomized controlled trial, Predictive Value of Tests, law, Mendelian randomization, Animals, Humans, Medicine, Predictive testing, Randomized Controlled Trials as Topic, biology, business.industry, Biochemistry (medical), C-reactive protein, Critical appraisal, C-Reactive Protein, Genetic epidemiology, Immunology, biology.protein, Observational study, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

Background: The hepatocyte-derived acute-phase reactant C-reactive protein (CRP) has been the subject of intense research over the last 2 decades for its possible role in the pathogenesis of cardiovascular diseases. This research has spawned interest in the use of the blood concentration of CRP for predicting a first coronary heart disease (CHD) event, which has been made possible with the development of high-sensitivity CRP (hsCRP) assays that can measure the typically low concentrations of CRP that circulate in the absence of an overt infective or inflammatory episode, and as a potential causal factor that might be targeted therapeutically. The research has encompassed observational and genetic epidemiology, basic science studies with cells and tissues, experiments with animal models and humans, and randomized trials (although not of specific CRP-lowering therapies as yet). Content: We focus on investigations of the potential role of small differences in basal hsCRP concentration seen in healthy individuals and the relationship of such differences to the long-term risk of a first CHD event, rather than on research devoted to the high acute-phase CRP concentrations, which occur after acute atherothrombotic events and can influence the severity of ischemic tissue damage and the subsequent prognosis. We concentrate mainly on research findings at the translational interface and draw on evidence from human observational and genetic epidemiology, as well as from randomized trials. Conclusions: As the field matures from one of discovery to an evaluative science, the development of possible clinical applications requires a sharpening of focus on and a critical appraisal of the strengths and deficiencies of the accumulated evidence. Such assessments require attention to both the current state of affairs and the design of future research, so that the existing uncertainties about the utility of CRP in predicting CHD and its role in causing this disease can be resolved.

Published
2009
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37. Inflammatory biomarkers and the prediction of coronary events among people at intermediate risk: the EPIC-Norfolk prospective population study

Author

Jean-Pierre Després, Ewa Ninio, Mélanie Côté, Jamal S. Rana, Kay-Tee Khaw, J.J.P. Kastelein, S.M. Boekholdt, M. S. Sandhu, Aeilko H. Zwinderman, Philippa J. Talmud, Nicholas J. Wareham, Faculteit der Geneeskunde, Amsterdam Cardiovascular Sciences, Vascular Medicine, Amsterdam Public Health, Epidemiology and Data Science, and Cardiology

Subjects
Male, medicine.medical_specialty, Population, Coronary Artery Disease, 030204 cardiovascular system & hematology, Group II Phospholipases A2, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Risk factor, education, Prospective cohort study, Aged, Peroxidase, Inflammation, education.field_of_study, Framingham Risk Score, Chemotactic Factors, business.industry, Aryldialkylphosphatase, Case-control study, Fibrinogen, Middle Aged, 3. Good health, Surgery, C-Reactive Protein, Case-Control Studies, Cohort, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Population study, Female, Adiponectin, Cardiology and Cardiovascular Medicine, Risk assessment, business, Biomarkers
Abstract

Objective: To evaluate the role of the inflammatory biomarkers C-reactive protein (CRP), myeloperoxidase, paraoxonase, secretory phospholipase A2 group IIA (sPLA2), lipoprotein-associated phospholipase A2, fibrinogen, macrophage chemoattractant protein-1 and adiponectin, in predicting the risk of coronary heart disease (CHD) among people estimated to be at intermediate risk according to the Framingham Risk Score (FRS). Design: Prospective case–control study nested in EPIC-Norfolk cohort. Setting: Norfolk, UK. Patients: Apparently healthy men and women aged 45–79 years. Main outcome measures: Risk of future coronary artery disease. Results: For participants predicted to be at intermediate risk by the FRS, the highest c statistics were observed for FRS plus CRP (0.61, 95% CI 0.57 to 0.65) and for FRS plus sPLA2 (0.56, 95% CI 0.52 to 0.6). Net correct reclassification of cases and controls for each marker was assessed for people across the entire risk spectrum and again for people at intermediate risk only. The largest differences were observed for CRP, 12.0% net reclassification improvement in the entire risk spectrum and 28.4% net reclassification improvement in the intermediate-risk group and for sPLA2, the net reclassification improvement was 6.4% in the entire risk spectrum and 16.3% in the intermediate-risk group. Conclusions: The discriminatory potential of inflammatory biomarkers was substantially different when analysed across the entire risk spectrum compared with the subgroup of people at intermediate risk.

Published
2009
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38. Xbal polymorphism of the apolipoprotein B gene influences plasma lipid response to diet intervention

Author

Seppo Sarna, Pirjo Pietinen, Chun-Fang Xu, T Hämäläinen, J. K. Huttunen, Matti J. Tikkanen, Philippa J. Talmud, and Steve E. Humphries

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Apolipoprotein B, Blood lipids, Coronary Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Internal medicine, Blood plasma, Genetics, medicine, Humans, Alleles, Finland, Genetics (clinical), Apolipoproteins B, 030304 developmental biology, 0303 health sciences, Polymorphism, Genetic, biology, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Middle Aged, Endocrinology, chemistry, Low-density lipoprotein, biology.protein, Female, lipids (amino acids, peptides, and proteins), Polymorphism, Restriction Fragment Length
Abstract

Fresh blood samples were collected from 103 North Karelians who had in 1981-84 participated in dietary intervention studies and analysis of the XbaI restriction fragment length polymorphism (RFLP) of apolipoprotein B (apoB) was carried out. Reanalysis of the original plasma lipid and apolipoprotein data indicated that while baseline concentrations did not differ significantly between genotypes, the response to a low-fat, low-cholesterol diet was influenced by apoB XbaI genotype: reductions in total and low density lipoprotein (LDL) cholesterol, apoB and high density lipoprotein (HDL) cholesterol were greater in subjects homo- or heterozygous for the presence of the XbaI cutting site (X1X2 or X2X2 genotype, designated X2+) as compared to those lacking the cutting site (X1X1 genotype, designated X2-). The corresponding average reductions induced by dietary intervention in X2+ and X2- subjects were: for total cholesterol 1.30 and 0.99 mmol/l (p = 0.036), for LDL cholesterol 1.04 and 0.78 mmol/l (p = 0.049), for apoB 18.3 and 8.1 mg/100 ml (p = 0.012) and for HDL cholesterol 0.26 and 0.17 mmol/l (p = 0.008).

Published
2008
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39. Cardiovascular disease risk prediction using genetic information (gene scores): is it really informative?

Author

Nikos Yiannakouris, Philippa J. Talmud, and Steve E. Humphries

Subjects
Candidate gene, Endocrinology, Diabetes and Metabolism, MEDLINE, Bioinformatics, Polymorphism, Single Nucleotide, Risk Factors, Genotype, Genetics, Genetic predisposition, Humans, Medicine, Myocardial infarction, Allele, Risk factor, Molecular Biology, Gene, Alleles, Nutrition and Dietetics, business.industry, Cell Biology, medicine.disease, Cardiovascular Diseases, Cardiology and Cardiovascular Medicine, business, Algorithms
Abstract

DNA-based tests for assessment of genetic predisposition to coronary heart disease need to provide information over and above that of conventional risk factors. The efficacy of selected 'candidate' gene loci in risk algorithms, to improve the predictive accuracy for coronary heart disease, remains to be demonstrated.Although many candidate genes for coronary heart disease have been tested, the optimal set of risk genotypes has yet to be identified. There is only a relatively modest risk to be expected in association with any single genotype, published estimates are in the range of 1.12-1.73. Thus the risk associated with any one genotype is modest, but, in combination, selected genotypes may be associated with a clinically significant risk. Since the allele frequency for many of these variants is high, many individuals will carry several 'risk alleles'. A small number of selected single nucleotide polymorphisms should complement the conventional risk factors to identify high-risk individuals in whom correction of 'modifiable risk factors' through lifestyle interventions or medication would be most beneficial.As our understanding of how genetic variation impacts on common diseases advances, the novel loci identified by genome-wide association scans associated with disease risk will rapidly improve these risk algorithms.

Published
2008
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40. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. 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Adrienne, Halperin, Eran, Li, Mingyao, Musunuru, Kiran, Preuss, Michael, Schillert, Arne, Thorleifsson, Gudmar, Wells, George A., Holm, Hilma, Roberts, Robert, Stewart, Alexandre F. R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016
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41. Rare APOA5 mutations—Clinical consequences, metabolic and functional effects

Author

Philippa J. Talmud

Subjects
Genetics, Genetically modified mouse, medicine.medical_specialty, Mutation, Apolipoprotein B, biology, medicine.disease_cause, Penetrance, Phenotype, Endocrinology, Internal medicine, medicine, biology.protein, Allele, Cardiology and Cardiovascular Medicine, Gene, Lipoprotein
Abstract

In 2001, a gene encoding a novel apolipoprotein (apo), APOA5, was identified by comparative human/mouse sequencing. The encoded protein, apoAV, had been missed in routine apolipoprotein identification because it occurs at very low plasma concentrations and only DNA analysis led to its identification. Knockout and transgenic mouse models of apoAV showed an inverse relationship with plasma triglyceride levels. In human studies, common APOA5 variants have shown near consistent association with elevated plasma TG levels, confirming apoAV as playing a role in human triglyceride metabolism. Based on mouse knockout models it was predicted that individuals with rare mutations in APOA5 would present with severe hypertriglyceridaemia and apoAV deficiency. However, considering the small number of mutation carriers identified to date, the mode of inheritance is variable and in the recessive form TG levels are within the normal range, and apoAV deficiency only occurs in the homozygous state. Furthermore, penetrance of the mutations is low and appears to require co-inheritance of a common APOA5 TG-raising allele as well as environmental factors for expression of the hypertriglyceridaemia. In this review the clinical and metabolic consequences and phenotype of the three APOA5 mutations reported to date, which lead to premature truncations of apoAV are described. The insight these truncated protein give to the structure-function relationship of apoAV is explored and the relative importance of plasma and liver apoAV discussed.

Published
2007
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42. Common variants of apolipoprotein A-IV differ in their ability to inhibit low density lipoprotein oxidation

Author

Wendy Putt, Jane L. Roberts, David S. Leake, Andrew B. Gerry, Wai-man R. Wong, Richard B. Weinberg, Philippa J. Talmud, and Steve E. Humphries

Subjects
Copper Sulfate, Antioxidant, Apolipoprotein B, G protein, medicine.medical_treatment, Amidines, Apolipoprotein A-IV, medicine.disease_cause, Antioxidants, Lipid peroxidation, chemistry.chemical_compound, polycyclic compounds, medicine, Humans, Protein Isoforms, Apolipoproteins A, biology, Wild type, nutritional and metabolic diseases, Molecular biology, Lipoproteins, LDL, Biochemistry, chemistry, Apolipoprotein A-V, Low-density lipoprotein, Mutagenesis, Site-Directed, biology.protein, lipids (amino acids, peptides, and proteins), Lipid Peroxidation, Cardiology and Cardiovascular Medicine, Oxidation-Reduction, Oxidative stress
Abstract

Apolipoprotein A-IV (apoA-IV) inhibits lipid peroxidation, thus demonstrating potential anti-atherogenic properties. The aim of this study was to investigate how the inhibition of low density lipoprotein (LDL) oxidation was influenced by common apoA-IV isoforms. Recombinant wild type apoA-IV (100 mu g/ml) significantly inhibited the oxidation of LDL (50 mu g protein/ml) by 5 mu M CuSO4 (P < 0.005), but not by 100 mu M CuSO4, suggesting that it may act by binding copper ions. ApoA-IV also inhibited the oxidation of LDL by the water-soluble free-radical generator 2,2'-azobis(amidinopropane) dihydrochloride (AAPH; I mM), as shown by the two-fold increase in the time for half maximal conjugated diene formation (T-1/2; P < 0.05) suggesting it can also scavenge free radicals in the aqueous phase. Compared to wild type apoA-IV, apoA-IV-S347 decreased T-1/2 by 15% (P = 0.036) and apoA-IV-H360 increased T-1/2 by 18% (P = 0.046). All apoA-IV isoforms increased the relative electrophoretic mobility of native LDL, suggesting apoA-IV can bind to LDL and acts as a site-specific antioxidant. The reduced inhibition of LDL oxidation by apoA-IV-S347 compared to wild type apoA-IV may account for the previous association of the APOA4 S347 variant with increased CHD risk and oxidative stress. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Published
2007
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43. The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease

Author

Alistair S. Hall, Philippa J. Talmud, Steve E. Humphries, Hugh Montgomery, Anthony J. Balmforth, Jackie A. Cooper, Khaled Alfakih, David M. Flavell, and Mohan U. Sivananthan

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Coronary Disease, Left ventricular hypertrophy, chemistry.chemical_compound, Gene Frequency, Risk Factors, Intensive care, Internal medicine, Serine, medicine, Humans, Prospective Studies, cardiovascular diseases, Risk factor, Triglycerides, Lipoprotein lipase, Framingham Risk Score, Triglyceride, business.industry, Myocardium, Fatty Acids, Homozygote, General Medicine, Odds ratio, Middle Aged, medicine.disease, Lipids, Lipoprotein Lipase, Apolipoproteins, Endocrinology, Blood pressure, chemistry, Hypertension, Female, Hypertrophy, Left Ventricular, business
Abstract

LVH [LV (left ventricular) hypertrophy] is an independent risk factor for CHD (coronary heart disease). During LVH, the preferred cardiac energy substrate switches from FAs (fatty acids) to glucose. LPL (lipoprotein lipase) is the key enzyme in triacylglycerol (triglyceride) hydrolysis and supplies FAs to the heart. To investigate whether substrate utilization influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-X447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. In a cohort of 190 hypertensive subjects, LPL X447 was associated with a greater LV mass index [85.2 (1.7) in S/S compared with 91.1 (3.4) in S/X+X/X; P=0.01], but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with than those without LVH {0.14 [95% CI (confidence interval), 0.08–0.19] compared with 0.07 (95% CI, 0.05–0.10) respectively; odds ratio, 2.52 (95% CI, 1.17–5.40), P=0.02}. The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged U.K. men (n=2716). In normotensive individuals, compared with S447 homozygotes, X447 carriers were protected from CHD risk [HR (hazard ratio), 0.48 (95% CI, 0.23–1.00); P=0.05], whereas, in the hypertensives, X447 carriers had increased risk [HR, 1.54 (95% CI, 1.13–2.09) for S/S (P=0.006) and 2.30 (95% CI, 1.53–3.45) for X447+ (P

Published
2007
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44. Candidate Gene Genotypes, Along with Conventional Risk Factor Assessment, Improve Estimation of Coronary Heart Disease Risk in Healthy UK Men

Author

George J. Miller, Jackie A. Cooper, Philippa J. Talmud, and Steve E. Humphries

Subjects
Male, Risk, Oncology, Apolipoprotein E, medicine.medical_specialty, Candidate gene, Pathology, Genotype, Clinical Biochemistry, Population, Coronary Disease, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Predictive Value of Tests, Reference Values, Risk Factors, Polymorphism (computer science), Internal medicine, medicine, Humans, False Positive Reactions, Prospective Studies, Myocardial infarction, Risk factor, education, education.field_of_study, business.industry, Cholesterol, Smoking, Biochemistry (medical), Middle Aged, medicine.disease, United Kingdom, Blood pressure, ROC Curve, chemistry, Multivariate Analysis, business, Algorithms
Abstract

Background: One of the aims of cardiovascular genetics is to test the efficacy of the use of genetic information to predict cardiovascular risk. We therefore investigated whether inclusion of a set of common variants in candidate genes along with conventional risk factor (CRF) assessment enhanced coronary heart disease (CHD)-risk algorithms. Methods: We followed middle-aged men in the prospective Northwick Park Heart Study II (NPHSII) for 10.8 years and analyzed complete trait and genotype information available on 2057 men (183 CHD events). Results: Of the 12 genes previously associated with CHD risk, in stepwise multivariate risk analysis, uncoupling protein 2 (UCP2; P = 0.0001), apolipoprotein E (APOE; P = 0.0003), lipoprotein lipase (LPL; P = 0.007), and apolipoprotein AIV (APOA4; P = 0.04) remained in the model. Their combined area under the ROC curve (AROC) was 0.62 (0.58–0.66) [12.6% detection rate for a 5% false positive rate (DR5)]. The AROC for the CRFs age, triglyceride, cholesterol, systolic blood pressure, and smoking was 0.66 (0.61–0.70) (DR5 = 14.2%). Combining CRFs and genotypes significantly improved discrimination (P = 0.001). Inclusion of previously demonstrated interactions of smoking with LPL, interleukin-6 (IL6), and platelet/endothelial cell adhesion molecule (PECAM1) genotypes increased the AROC to 0.72 (0.68–0.76) for a DR5 of 19.1% (P = 0.01 vs CRF combined with genotypes). Conclusions: For a modest panel of selected genotypes, CHD-risk estimates incorporating CRFs and genotype–risk factor interactions were more effective than risk estimates that used CRFs alone.

Published
2007
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45. Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia

Author

Wu-Wei Zeng, Geesje M. Dallinga-Thie, Aaron Isaacs, Anton F. H. Stalenhoef, Cornelia M. van Duijn, Gerly M. van der Vleuten, Ewoud ter Avest, Philippa J. Talmud, Jacqueline de Graaf, Faculteit Medische Wetenschappen/UMCG, Epidemiology, Internal Medicine, Vascular Medicine, and Experimental Vascular Medicine

Subjects
Lipoproteins, LDL/blood, Male, Apolipoprotein B, Triglyceride level, Intima-media thickness, Hyperlipidemia, Familial Combined, Cardiovascular Diseases/blood, Vascular medicine and diabetes [UMCN 2.2], Hyperlipidemia, Familial Combined/blood, chemistry.chemical_compound, Polymorphism (computer science), Hyperlipidemia, Haplotype, Netherlands, Ultrasonography, Genetics, Cholesterol, HDL/blood, Cardiovascular diseases [NCEBP 14], biology, medicine.diagnostic_test, Homozygote, Remnant-like particle, Middle Aged, LDL/blood, Lipoproteins, LDL, APOA5 gene, Triglycerides/blood, Cholesterol, Carotid Arteries, Cardiovascular Diseases, HDL/blood, Population study, Molecular Medicine, Female, lipids (amino acids, peptides, and proteins), Adult, medicine.medical_specialty, Health aging / healthy living [IGMD 5], Familial combined hyperlipidemia, Lipoproteins, Risk Assessment, Genetic, Apolipoproteins A/genetics, Internal medicine, medicine, Humans, Familial Combined/blood, Genetic Predisposition to Disease, Polymorphism, Allele, Carotid Arteries/diagnostic imaging, Molecular Biology, Apolipoproteins A, Triglycerides, Polymorphism, Genetic, Cholesterol, HDL, medicine.disease, Endocrinology, chemistry, Haplotypes, Apolipoprotein A-V, biology.protein, Lipid profile
Abstract

Contains fulltext : 53623.pdf (Publisher’s version ) (Closed access) BACKGROUND: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. MATERIALS AND METHODS: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (-1131T>C and S19W) were genotyped. RESULTS: Haplotype analysis of APOA5 showed an association with FCH (p=0.029), total cholesterol (p=0.031), triglycerides (p

Published
2007
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47. Apolipoprotein A-V, triglycerides and risk of coronary artery disease: the prospective Epic-Norfolk Population Study

Author

Stefan F C Vaessen, Sheila Bingham, Nicholas J. Wareham, Barbara A. Hutten, Manjinder S. Sandhu, Kay-Tee Khaw, S. Matthijs Boekholdt, Albert K. Groen, John J.P. Kastelein, Hiroaki Hattori, Philippa J. Talmud, Steve E. Humphries, Frank G. Schaap, Robert Luben, J. A. Kuivenhoven, J. Palmen, Experimental Vascular Medicine, Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Amsterdam Cardiovascular Sciences, Medical Biochemistry, Epidemiology and Data Science, Cardiology, and Vascular Medicine

Subjects
Male, medicine.medical_specialty, Linkage disequilibrium, Genotype, Apolipoprotein B, Single-nucleotide polymorphism, QD415-436, Coronary Artery Disease, Polymorphism, Single Nucleotide, Biochemistry, Linkage Disequilibrium, Endocrinology, Gene Frequency, single nucleotide polymorphism, Risk Factors, Internal medicine, polycyclic compounds, medicine, Humans, Prospective Studies, Allele frequency, Apolipoproteins A, Triglycerides, Aged, biology, Case-control study, nutritional and metabolic diseases, Cell Biology, European Prospective Investigation into Cancer and Nutrition, Middle Aged, United Kingdom, Minor allele frequency, Apolipoproteins, Apolipoprotein A-V, Case-Control Studies, Multivariate Analysis, biology.protein, Population study, epidemiology, Female, lipids (amino acids, peptides, and proteins)
Abstract

In mouse models, apolipoprotein A-V (apoA-V) exhibits triglyceride (TG)-lowering effects. We investigated the apoA-V/TG relationship and the association of apoA-V with coronary artery disease (CAD) risk by determining serum apoA-V levels and genotypes in a nested case-control (n = 1,034/2,031) study. Both univariate and multivariate apoA-V levels showed no association with future CAD (P = 0.4 and 0.5, respectively). Unexpectedly, there was a significant positive correlation between serum apoA-V and TG in men and women (r = 0.36 and 0.28, respectively, P < 0.001 each) but a negative correlation between apoA-V and LPL mass (r = −0.14 and −0.12 for men and women respectively, P < 0.001 each). The frequency of the c.56C>G polymorphism did not differ between cases and controls despite significant positive association of c.56G with both apoA-V and TG levels. For −1131T>C, the minor allele was significantly associated with lower apoA-V yet higher TG levels and was overrepresented in cases (P = 0.047). The association of −1131T>C with CAD risk, however, was independent of apoA-V levels and likely acts through linkage disequilibrium with APOC3 variants. The positive correlation of apoA-V levels with TG levels, negative correlation with LPL levels, and lack of association with CAD risk highlight the need for further human studies to clarify the role of apoA-V.

Published
2006
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48. Interaction between insulin (VNTR) and hepatic lipase (LIPC−514C>T) variants on the response to an oral glucose tolerance test in the EARSII group of young healthy men

Author

Philippa J. Talmud, Steve E. Humphries, Hans Jansen, Dawn M. Waterworth, Viviane Nicaud, and Clinical Chemistry

Subjects
Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Minisatellite Repeats, Type 2 diabetes, Biology, Insulin resistance, Gene interaction, Polymorphism (computer science), Internal medicine, medicine, Humans, Insulin, Genetic Predisposition to Disease, Apolipoproteins C, Exercise, Molecular Biology, Apolipoprotein C-III, Glucose tolerance test, medicine.diagnostic_test, Genetic Variation, Hepatic lipase, Lipase, Glucose Tolerance Test, medicine.disease, Europe, Variable number tandem repeat, Glucose, Endocrinology, Molecular Medicine, Insulin Resistance
Abstract

Insulin resistance is polygenic in origin, and can be observed at an early age. We have shown that variations in APOC3−482T>C and hepatic lipase (LIPC)-514C>T), individually (APOC3 alone) and interactively, modulate insulin and glucose levels after an OGTT in young healthy men participating in the European Atherosclerosis Research Study II (EARSII). Variation in the insulin gene (INS) variable number tandem repeat (VNTR) has been found to predispose to type 1 and type 2 diabetes. We have evaluated the HphI site 23 bp upstream of the INS gene (a surrogate marker for the VNTR) in EARSII (n=822), to determine if variation in INS contributes to insulin resistance. Carriers of the INS VNTR class III (HphI−) allele (frequency=0.29 (95%CI 0.27, 0.31)) had significantly higher 60-min insulin concentrations after the OGTT (P=0.014) and a marginally higher AUC insulin (P=0.07), compared to class I (HphI+) homozygotes. However, this effect on AUC insulin was modified by the level of physical activity, displaying significant gene:environment interaction (P=0.03). We tested for gene:gene interaction between the INS VNTR and both the LIPC−514C>T and APOC3−482T>C. While there was a significant interaction between INS VNTR and LIPC−514C>T on AUC glucose (P=0.013) and on AUC insulin (P=0.015), there was no interaction with APOC3−482T>C. Thus, despite a modest effect of the INS VNTR alone, the influence of this variant on insulin sensitivity was modified by gene:environment and gene:gene interactions, illustrating the biological complexity of insulin resistance.

Published
2005
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49. Investigation into the role of the hormone sensitive lipase −60C>G promoter variant in morbid obesity

Author

J. Palmen, Ulrike Beisiegel, Anna Maria Wolf, and Philippa J. Talmud

Subjects
Adult, Blood Glucose, Leptin, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, Hormone-sensitive lipase, Biology, Cohort Studies, Gene Frequency, Internal medicine, medicine, Humans, Insulin, Glucose homeostasis, Allele, Promoter Regions, Genetic, Fatty acid homeostasis, Allele frequency, Nutrition and Dietetics, Genetic Variation, Lipase, Middle Aged, Lipid Metabolism, medicine.disease, Obesity, Obesity, Morbid, Endocrinology, Cohort, Female, Cardiology and Cardiovascular Medicine
Abstract

Summary Background Hormone sensitive lipase (HSL) plays a central role in free fatty acid homeostasis in adipose tissue and in pancreatic β-cells, where it contributes to the control of insulin secretion by generating long-chain fatty acids. Aim We examined the frequency and association of the functional HSL promoter variant, −60C>G, in a German cohort of morbidly obese women ( N =239) and men ( N =55) and compared the frequency to a cohort of 199 blood donors, recruited from the same region. Results The rare allele frequency of −60C>G, in the obese individuals was significantly lower 0.031 (95% CI 0.02, 0.04), than that in the blood donors 0.061 (95% CI 0.04, 0.08) p =0.05. The association of the HSL −60C>G with lipid and glucose parameters was examined in the obese women (there were too few men for comparative analysis). In the obese women, those heterozygous for the −60G had significantly higher glucose levels compared to CC women, 142.71 (±16.23) mg/dl vs. 110.34 (±1.79) mg/dl, respectively ( p =0.0001). There was no statistically significant difference in other parameters. Conclusion This study confirms a role for HSL in glucose homeostasis and the reduced frequency of the low expressing −60G promoter variant in obese individuals, together with existing published data, suggests that this allele might be protective against obesity.

Published
2005
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50. No APOEε4 effect on coronary heart disease risk in a cohort with low smoking prevalence: the Whitehall II study

Author

Eric J. Brunner, S Martin, Sarah J Lewis, Jayshree Acharya, Philippa J. Talmud, Steve E. Humphries, Michael Marmot, and Emma Hawe

Subjects
medicine.medical_specialty, business.industry, Incidence (epidemiology), Context (language use), Odds ratio, medicine.disease, Surgery, Internal medicine, Cohort, medicine, lipids (amino acids, peptides, and proteins), Myocardial infarction, Risk factor, Cardiology and Cardiovascular Medicine, business, Prospective cohort study, Cohort study
Abstract

Carriers of the APOEepsilon4 allele have consistently shown higher, and epsilon2 carriers have lower, plasma cholesterol and coronary heart disease (CHD) risk compared with epsilon3 homozygotes. An epsilon4:smoking interaction was observed in NPHSII, consistent with context dependency of the epsilon4 effect on CHD risk. In this study, APOE genotype was determined in 3787 male British civil servants followed for fatal and non-fatal myocardial infarction for median of 5.8 years, with 159 validated CHD events. APOE genotype was associated with expected effects on lipid traits (all P

Published
2004
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