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8 results on '"Stitziel, N.O."'

1. Semi-automated assembly of high-quality diploid human reference genomes

Author

Jarvis, E.D., Formenti, G., Rhie, A., Guarracino, A., Yang, C., Wood, J., Tracey, A., Thibaud-Nissen, F., Vollger, M.R., Porubsky, D., Cheng, H., Asri, M., Logsdon, G.A., Carnevali, P., Chaisson, M.J.P., Chin, C.S., Cody, S., Collins, J., Ebert, P., Escalona, M., Fedrigo, O., Fulton, R.S., Fulton, L.L., Garg, S., Gerton, J.L., Ghurye, J., Granat, A., Green, R.E., Harvey, W., Hasenfeld, P., Hastie, A., Haukness, M., Jaeger, E.B., Jain, M., Kirsche, M., Kolmogorov, M., Korbel, J.O., Koren, S., Korlach, J., Lee, J., Li, D., Lindsay, T., Lucas, J., Luo, F., Marschall, T., Mitchell, M.W., McDaniel, J., Nie, F., Olsen, H.E., Olson, N.D., Pesout, T., Potapova, T., Puiu, D., Regier, A., Ruan, J., Salzberg, S.L., Sanders, A.D., Schatz, M.C., Schmitt, A., Schneider, V.A., Selvaraj, S., Shafin, K., Shumate, A., Stitziel, N.O., Stober, C., Torrance, J., Wagner, J., Wang, J., Wenger, A., Xiao, C., Zimin, A.V., Zhang, G., Wang, T., Li, H., Garrison, E., Haussler, D., Hall, I., Zook, J.M., Eichler, E.E., Phillippy, A.M., Paten, B., Howe, K., and Miga, K.H.

Subjects
Cancer Research, Haplotypes, Genome, Human, Humans, Chromosome Mapping, High-Throughput Nucleotide Sequencing, Chromosomes, Human, Genetic Variation, Sequence Analysis, DNA, Genomics, Reference Standards, Diploidy
Abstract

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted societysup1,2/sup. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individualssup3,4/sup. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genomesup5/sup. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversitysup6/sup. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.

Published
2021

2. Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Author

Webb, T.R., Erdmann, J., Stirrups, K.E., Stitziel, N.O., Masca, N.G.D., Jansen, H., Kanoni, S., Nelson, C.P., Ferrario, P.G., Konig, I.R., Eicher, J.D., Johnson, A.D., Hamby, S.E., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., Bjorkegren, J.L.M., Weeke, P.E., Auer, P.L., Schick, U.M., Lu, Y.C., Zhang, H., Dube, M.P., Goel, A., Farrall, M., Peloso, G.M., Won, H.H., R. do, Iperen, E. van, Kruppa, J., Mahajan, A., Scott, R.A., Willenborg, C., Braund, P.S., Capelleveen, J.C. van, Doney, A.S.F., Donnelly, L.A., Asselta, R., Merlini, P.A., Duga, S., Marziliano, N., Denny, J.C., Shaffer, C., El-Mokhtari, N.E., Franke, A., Heilmann, S., Hengstenberg, C., Hoffmann, P., Holmen, O.L., Hveem, K., Jansson, J.H., Jockel, K.H., Kessler, T., Kriebel, J., Laugwitz, K.L., Marouli, E., Martinelli, N., McCarthy, M.I., Zuydam, N.R. van, Meisinger, C., Esko, T., Mihailov, E., Escher, S.A., Alver, M., Moebus, S., Morris, A.D., Virtamo, J., Nikpay, M., Olivieri, O., Provost, S., AlQarawi, A., Robertson, N.R., Akinsansya, K.O., Reilly, D.F., Vogt, T.F., Yin, W., Asselbergs, F.W., Kooperberg, C., Jackson, R.D., Stahl, E., Muller-Nurasyid, M., Strauch, K., Varga, T.V., Waldenberger, M., Zeng, L.Y., Chowdhury, R., Salomaa, V., Ford, I., Jukema, J.W., Amouyel, P., Kontto, J., Nordestgaard, B.G., Ferrieres, J., Saleheen, D., Sattar, N., Surendran, P., Wagner, A., Young, R., Howson, J.M.M., Butterworth, A.S., Danesh, J., Ardissino, D., Bottinger, E.P., Erbel, R., Franks, P.W., Girelli, D., Hall, A.S., Hovingh, G.K., Kastrati, A., Lieb, W., Meitinger, T., Kraus, W.E., Shah, S.H., McPherson, R., Orho-Melander, M., Melander, O., Metspalu, A., Palmer, C.N.A., Peters, A., Rader, D.J., Reilly, M.P., Loos, R.J.F., Reiner, A.P., Roden, D.M., Tardif, J.C., Thompson, J.R., Wareham, N.J., Watkins, H., Willer, C.J., Samani, N.J., Schunkert, H., Deloukas, P., Kathiresan, S., Wellcome Trust Case Control, MORGAM Investigators, and Myocardial Infarction Genetics

Subjects
expression quantitative trait loci, single nucleotide polymorphism, cholesteryl ester transfer protein, genome-wide association, genetics
Abstract

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Published
2017

3. Common and Rare Genetic Variation in CCR2, CCR5, or CX3CR1 and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits

Author

Golbus, J.R., Stitziel, N.O., Zhao, W., Xue, C., Farrall, M, McPherson, R., Erdmann, J., Deloukas, P., Watkins, H., Schunkert, H., Samani, N.J., Saleheen, D., Kathiresan, S., Reilly, M.P., EUMODIC Consortium (Meitinger, T., Peters, A., and Gieger, C.)

Subjects
0301 basic medicine, Receptors, CCR5, Multifunction cardiogram, Receptors, CCR2, CX3C Chemokine Receptor 1, Myocardial Infarction, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Gene Frequency, Risk Factors, Databases, Genetic, Genetics, SNP, Humans, Exome, Genetic Predisposition to Disease, Pakistan, International HapMap Project, Allele frequency, Genetics (clinical), Exome sequencing, Glucose Metabolism Disorders, Retrospective Studies, Europe, 030104 developmental biology, Phenotype, Receptors, Chemokine, Cardiology and Cardiovascular Medicine, atherosclerosis, diabetes mellitus, genetics, genome-wide association study, myocardial infarction, Genome-Wide Association Study
Abstract

Background— The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits. Methods and Results— We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2 , CCR5 , or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus. Conclusions— No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.

Published
2016

4. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Author

Zanoni, P., Khetarpal, S.A., Larach, D.B., Hancock-Cerutti, W.F., Millar, J.S., Cuchel, M., Derohannessian, S.L., Kontush, A., Surendran, P., Saleheen, D., Trompet, S., Jukema, J.W., de Craen, A.J., Deloukas, P., Sattar, N., Ford, I., Packard, C., Al Shafi Majumder, A., Alam, D.S., di Angelantonio, E., Abecasis, G., Chowdhury, R., Erdmann, J., Nørdestgaard, B.G., Nielsen, S.F., Tybjærg-Hansen, A., Schmidt, R.F., Kuulasmaa, K., Liu, D.J., Perola, M., Blankenberg, S., Salomaa, V., Männistö, S., Amouyel, P., Arveiler, D., Ferrieres, J., Müller-Nurasyid, M., Ferrario, M., Kee, F., Willer, C.J., Samani, N., Schunkert, H., Butterworth, A.S., Howson, J.M.M., Peloso, G.M., Stitziel, N.O., Danesh, J., Kathiresan, S., Rader, D.J., CHD Exome Consortium (), CARDIoGRAM Exome Consortium (), Global Lipids Genetics Consortium (), CHD Exome+ Consortium, CARDIoGRAM Exome Consortium, Global Lipids Genetics Consortium, Watson, S., Schmidt, E.M., Sengupta, S., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., Buchkovich, M.L., Mora, S., Beckmann, J.S., Bragg-Gresham, J.L., Chang, H.Y., Demirkan, A., Den Hertog, H.M., Do, R., Donnelly, L.A., Ehret, G.B., Esko, T., Feitosa, M.F., Ferreira, T., Fischer, K., Fontanillas, P., Fraser, R.M., Freitag, D.F., Gurdasani, D., Heikkilä, K., Hyppönen, E., Isaacs, A., Jackson, A.U., Johansson, Å., Johnson, T., Kaakinen, M., Kettunen, J., Kleber, M.E., Li, X., Luan, J., Lyytikäinen, L.P., Magnusson, P.K., Mangino, M., Mihailov, E., Montasser, M.E., Nolte, I.M., O'Connell, J.R., Palmer, C.D., Petersen, A.K., Sanna, S., Saxena, R., Service, S.K., Shah, S., Shungin, D., Sidore, C., Song, C., Strawbridge, R.J., Surakka, I., Tanaka, T., Teslovich, T.M., Thorleifsson, G., Van den Herik, E.G., Voight, B.F., Volcik, K.A., Waite, L.L., Wong, A., Wu, Y., Zhang, W., Absher, D., Asiki, G., Barroso, I., Been, L.F., Bolton, J.L., Bonnycastle, L.L., Brambilla, P., Burnett, M.S., Cesana, G., Dimitriou, M., Doney, A.S., Döring, A., Elliott, P., Epstein, S.E., Eyjolfsson, G.I., Gigante, B., Goodarzi, M.O., Grallert, H., Gravito, M.L., Groves, C.J., Hallmans, G., Hartikainen, A.L., Hayward, C., Hernandez, D., Hicks, A.A., Holm, H., Hung, Y.J., Illig, T., Jones, M.R., Kaleebu, P., Kastelein, J.J., Khaw, K.T., Kim, E., Klopp, N., Komulainen, P., Kumari, M., Langenberg, C., Lehtimäki, T., Lin, S.Y., Lindström, J., Loos, R.J., Mach, F., McArdle, W.L., Meisinger, C., Mitchell, B.D., Müller, G., Nagaraja, R., Narisu, N., Nieminen, T.V., Nsubuga, R.N., Olafsson, I., Ong, K.K., Palotie, A., Papamarkou, T., Pomilla, C., Pouta, A., Reilly, M.P., Ridker, P.M., Rivadeneira, F., Rudan, I., Ruokonen, A., Scharnagl, H., Seeley, J., Silander, K., Stancáková, A., Stirrups, K., Swift, A.J., Tiret, L., Uitterlinden, A.G., van Pelt, L.J., Vedantam, S., Wainwright, N., Wijmenga, C., Wild, S.H., Willemsen, G., Wilsgaard, T., Wilson, J.F., Young, E.H., Zhao, J.H., Adair, L.S., Arveiler, D., Assimes, T.L., Bandinelli, S., Bennett, F., Bochud, M., Boehm, B.O., Boomsma, D.I., Borecki, I.B., Bornstein, S.R., Bovet, P., Burnier, M., Campbell, H., Chakravarti, A., Chambers, J.C., Chen, Y.D., Collins, F.S., Cooper, R.S., Dedoussis, G., de Faire, U., Feranil, A.B., Ferrucci, L., Freimer, N.B., Gieger, C., Groop, L.C., Gudnason, V., Gyllensten, U., Hamsten, A., Harris, T.B., Hingorani, A., Hirschhorn, J.N., Hofman, A., Hovingh, G.K., Hsiung, C.A., Humphries, S.E., Hunt, S.C., Hveem, K., Iribarren, C., Järvelin, M.R., Jula, A., Kähönen, M., Kaprio, J., Kesäniemi, A., Kivimaki, M., Kooner, J.S., Koudstaal, P.J., Krauss, R.M., Kuh, D., Kuusisto, J., Kyvik, K.O., Laakso, M., Lakka, T.A., Lind, L., Lindgren, C.M., Martin, N.G., März, W., McCarthy, M.I., McKenzie, C.A., Meneton, P., Metspalu, A., Moilanen, L., Morris, A.D., Munroe, P.B., Njølstad, I., Pedersen, N.L., Power, C., Pramstaller, P.P., Price, J.F., Psaty, B.M., Quertermous, T., Rauramaa, R., Salomaa, V., Sanghera, D.K., Saramies, J., Schwarz, P.E., Sheu, W.H., Shuldiner, A.R., Siegbahn, A., Spector, T.D., Stefansson, K., Strachan, D.P., Tayo, B.O., Tremoli, E., Tuomilehto, J., Uusitupa, M., van Duijn, C.M., Vollenweider, P., Wallentin, L., Wareham, N.J., Whitfield, J.B., Wolffenbuttel, B.H., Ordovas, J.M., Boerwinkle, E., Palmer, C.N., Thorsteinsdottir, U., Chasman, D.I., Rotter, J.I., Franks, P.W., Riatti, S., Cupples, L.A., Sandhu, M.S., Rich, S.S., Boehnke, M., Deloukas, P., Mohlke, K.L., Ingelsson, E., Gu, D., Roberts, R., Watkins, H., Blankenberg, S., Clarke, R., Collins, R., Kim, B.J., McPherson, R., Nieminen, M.S., O'Donnell, C., Schreiber, S., Zalloua, P.A., Zanoni, P, Khetarpal, SA, Larach, DB, Hancock-Cerutti, WF, Rader, DJ, Hypponen, Elina, Biological Psychology, Khetarpal, S, Larach, D, Hancock Cerutti, W, Millar, J, Cuchel, M, Derohannessian, S, Kontush, A, Surendran, P, Saleheen, D, Trompet, S, Wouter Jukema, J, De Craen, A, Deloukas, P, Sattar, N, Ford, I, Packard, C, Majumder, A, Alam, D, Di Angelantonio, E, Abecasis, G, Chowdhury, R, Erdmann, J, Nordestgaard, B, Nielsen, S, Tybjærg Hansen, A, Ruth Frikke Schmidt, N, Kuulasmaa, K, Liu, D, Perola, M, Blankenberg, S, Salomaa, V, Männistö, S, Amouyel, P, Arveiler, D, Ferrieres, J, Möller Nurasyid, M, Ferrario, M, Kee, F, Willer, C, Samani, N, Schunkert, H, Butterworth, A, Howson, J, Peloso, G, Stitziel, N, Danesh, J, Kathiresan, S, Rader, D, Brambilla, P, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Netherlands Twin Register (NTR), 0301 basic medicine, Male, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Scavenger Receptors, DNA Mutational Analysis, Coronary Disease, 030204 cardiovascular system & hematology, scavenger receptor, chemistry.chemical_compound, Mice, 0302 clinical medicine, High-density lipoprotein, Receptor, increased atherosclerosis, levels of plasma, Multidisciplinary, Medicine (all), Homozygote, Scavenger Receptors, Class B, Middle Aged, 3. Good health, Cholesterol, Knockout mouse, Female, lipids (amino acids, peptides, and proteins), Human, Risk, medicine.medical_specialty, Heterozygote, HDL, Proline, Aged, Amino Acid Substitution, Animals, Cholesterol, HDL, Genetic Variation, Humans, Leucine, Protein Processing, Post-Translational, Article, DNA Mutational Analysi, Cholesterol, HDL/blood, Coronary Disease/blood, Coronary Disease/genetics, Leucine/genetics, Proline/genetics, Scavenger Receptors, Class B/genetics, Scavenger Receptors, Class B/metabolism, 03 medical and health sciences, Internal medicine, medicine, Scavenger receptor, Protein Processing, Animal, business.industry, Post-Translational, Heterozygote advantage, SCARB1, 030104 developmental biology, Endocrinology, chemistry, Class B, business, Lipoprotein
Abstract

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant). Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aa, Alam DS, Di Angelantonio E, Science (New York, N.Y.), 2016, vol. 351, no. 6278, pp. 1166-1171, 2016 Refereed/Peer-reviewed

Published
2016
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5. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

Author

Gregson, J.M. (John M.), Freitag, C.M. (Christine), Surendran, P. (Praveen), Stitziel, N.O. (Nathan), Chowdhury, R. (Rajiv), Burgess, S. (Stephen), Kaptoge, S. (Stephen), Gao, P. (Pei), Staley, J.R. (James R.), Willeit, J. (Johann), Nielsen, S.F. (Sune), Caslake, M. (Muriel), Trompet, S. (Stella), Polfus, L.M. (Linda M.), Kuulasmaa, K. (Kari), Kontto, J. (Jukka), Perola, M. (Markus), Blankenberg, S. (Stefan), Veronesi, G. (Giovanni), Gianfagna, F. (Francesco), Männistö, S. (Satu), Kimura, A. (Akinori), Lin, H. (Honghuang), Reilly, D.F. (Dermot F.), Gorski, M. (Mathias), Mijatovic, V. (Vladan), Munroe, P. (Patricia), Ehret, G.B. (Georg), Thompson, A. (Alex), Uria-Nickelsen, M. (Maria), Mälarstig, A. (Anders), Dehghan, A. (Abbas), Vogt, T.F. (Thomas F.), Sasaoka, T. (Taishi), Takeuchi, F. (Fumihiko), Kato, N. (Norihiro), Yamada, Y. (Yoshiji), Kee, F. (F.), Müller-Nurasyid, M. (Martina), Ferrieres, J. (Jean), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Salomaa, V. (Veikko), Boerwinkle, E.A. (Eric), Thompson, S.G. (Simon), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Packard, C.J. (Chris J.), Shafi Majumder, A.A. (Abdulla Al), Alam, D.S. (Dewan S.), Deloukas, P. (Panagiotis), Schunkert, H. (Heribert), Samani, N.J. (Nilesh), Kathiresan, S. (Sekar), Nordestgaard, B.G. (Børge), Saleheen, D. (Danish), Howson, J.M.M. (Joanna M.M.), Angelantonio, E. (Emanuele) di, Butterworth, A.S. (Adam), Danesh, J. (John), Gregson, J.M. (John M.), Freitag, C.M. (Christine), Surendran, P. (Praveen), Stitziel, N.O. (Nathan), Chowdhury, R. (Rajiv), Burgess, S. (Stephen), Kaptoge, S. (Stephen), Gao, P. (Pei), Staley, J.R. (James R.), Willeit, J. (Johann), Nielsen, S.F. (Sune), Caslake, M. (Muriel), Trompet, S. (Stella), Polfus, L.M. (Linda M.), Kuulasmaa, K. (Kari), Kontto, J. (Jukka), Perola, M. (Markus), Blankenberg, S. (Stefan), Veronesi, G. (Giovanni), Gianfagna, F. (Francesco), Männistö, S. (Satu), Kimura, A. (Akinori), Lin, H. (Honghuang), Reilly, D.F. (Dermot F.), Gorski, M. (Mathias), Mijatovic, V. (Vladan), Munroe, P. (Patricia), Ehret, G.B. (Georg), Thompson, A. (Alex), Uria-Nickelsen, M. (Maria), Mälarstig, A. (Anders), Dehghan, A. (Abbas), Vogt, T.F. (Thomas F.), Sasaoka, T. (Taishi), Takeuchi, F. (Fumihiko), Kato, N. (Norihiro), Yamada, Y. (Yoshiji), Kee, F. (F.), Müller-Nurasyid, M. (Martina), Ferrieres, J. (Jean), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Salomaa, V. (Veikko), Boerwinkle, E.A. (Eric), Thompson, S.G. (Simon), Ford, I. (Ian), Jukema, J.W. (Jan Wouter), Sattar, N. (Naveed), Packard, C.J. (Chris J.), Shafi Majumder, A.A. (Abdulla Al), Alam, D.S. (Dewan S.), Deloukas, P. (Panagiotis), Schunkert, H. (Heribert), Samani, N.J. (Nilesh), Kathiresan, S. (Sekar), Nordestgaard, B.G. (Børge), Saleheen, D. (Danish), Howson, J.M.M. (Joanna M.M.), Angelantonio, E. (Emanuele) di, Butterworth, A.S. (Adam), and Danesh, J. (John)

Abstract

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2 activity was decreased by 64% (p = 2.4 × 10-25) with carriage of any of the four loss-of-function variants, by 45% (p < 10-300) for every allele inherited at Val279Phe, and by 2.7% (p = 1.9 × 10-12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2 activity by 65% (p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a causal risk factor.

Published
2017
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6. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author

Liu, C. (Chunyu), Kraja, A. (Aldi), Smith, J.A. (Jennifer A), Brody, J.A. (Jennifer A.), Franceschini, N. (Nora), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Morrison, A.C. (Alanna), Lu, Y. (Yingchang), Weiss, S. (Stefan), Guo, X. (Xiuqing), Palmas, W. (Walter), Martin, L.W. (Lisa), Chen, Y.D. (Y.), Surendran, P. (Praveen), Drenos, F. (Fotios), Cook, J.P. (James P.), Auer, P. (Paul), Chu, A.Y. (Audrey), Giri, A. (Ayush), Zhao, W. (Wei), Jakobsdottir, M. (Margret), Lin, L.-A. (Li-An), Stafford, J.M. (Jeanette M.), Amin, N. (Najaf), Mei, H. (Hao), Yao, J. (Jiefen), Voorman, J.M. (Jeanine), Larson, M.G. (Martin), Grove, M.L. (Megan), Smith, A.V. (Albert Vernon), Hwang, S.J., Chen, H. (Han), Huan, T. (Tianxiao), Kosova, G. (Gulum), Stitziel, N.O. (Nathan), Kathiresan, S. (Sekar), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Deloukas, P. (Panagiotis), Li, M. (Man), Fuchsberger, C. (Christian), Pattaro, C. (Cristian), Gorski, M. (Mathias), Kooperberg, C. (Charles), Papanicolaou, G. (George), Rossouw, J.E. (Jacques E.), Faul, J.D. (Jessica D.), Kardia, S.L.R. (Sharon), Bouchard, C. (Claude), Raffel, L.J. (Leslie), Uitterlinden, A.G. (André G.), Franco, O.H. (Oscar), Vasan, R. (Ramachandran), O'Donnell, C.J. (Christopher), Taylor, K.D. (Kent), Liu, K.Y., Bottinger, E.P. (Erwin), Gottesman, R.F. (Rebecca), Daw, E.W. (E. Warwick), Giulianini, F. (Franco), Ganesh, S.K. (Santhi), Salfati, E. (Elias), Harris, T.B. (Tamara), Launer, L.J. (Lenore J.), Dörr, M. (Marcus), Felix, S.B. (Stephan), Rettig, R. (Rainer), Völzke, H. (Henry), Kim, E. (Eric), Lee, W.-J. (Wen-Jane), Lee, I.T., Sheu, W.H.-H. (Wayne H.-H.), Tsosie, K.S. (Krystal S.), Edwards, D.R.V. (Digna R. Velez), Liu, Y. (YongMei), Correa, A. (Adolfo), Weir, D.R. (David), Völker, U. (Uwe), Ridker, P.M. (Paul), Boerwinkle, E.A. (Eric), Gudnason, V. (Vilmundur), Reiner, A. (Alexander), Van Duijn, C.M. (Cornelia M.), Borecki, I.B. (Ingrid), Edwards, T.L. (Todd L.), Chakravarti, A. (Aravinda), Rotter, J.I. (Jerome I.), Psaty, B.M. (Bruce), Loos, R.J.F. (Ruth), Fornage, M. (Myriam), Ehret, G.B. (Georg), Newton-Cheh, C. (Christopher), Levy, D. (Daniel), Chasman, D.I. (Daniel), Liu, C. (Chunyu), Kraja, A. (Aldi), Smith, J.A. (Jennifer A), Brody, J.A. (Jennifer A.), Franceschini, N. (Nora), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Morrison, A.C. (Alanna), Lu, Y. (Yingchang), Weiss, S. (Stefan), Guo, X. (Xiuqing), Palmas, W. (Walter), Martin, L.W. (Lisa), Chen, Y.D. (Y.), Surendran, P. (Praveen), Drenos, F. (Fotios), Cook, J.P. (James P.), Auer, P. (Paul), Chu, A.Y. (Audrey), Giri, A. (Ayush), Zhao, W. (Wei), Jakobsdottir, M. (Margret), Lin, L.-A. (Li-An), Stafford, J.M. (Jeanette M.), Amin, N. (Najaf), Mei, H. (Hao), Yao, J. (Jiefen), Voorman, J.M. (Jeanine), Larson, M.G. (Martin), Grove, M.L. (Megan), Smith, A.V. (Albert Vernon), Hwang, S.J., Chen, H. (Han), Huan, T. (Tianxiao), Kosova, G. (Gulum), Stitziel, N.O. (Nathan), Kathiresan, S. (Sekar), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Deloukas, P. (Panagiotis), Li, M. (Man), Fuchsberger, C. (Christian), Pattaro, C. (Cristian), Gorski, M. (Mathias), Kooperberg, C. (Charles), Papanicolaou, G. (George), Rossouw, J.E. (Jacques E.), Faul, J.D. (Jessica D.), Kardia, S.L.R. (Sharon), Bouchard, C. (Claude), Raffel, L.J. (Leslie), Uitterlinden, A.G. (André G.), Franco, O.H. (Oscar), Vasan, R. (Ramachandran), O'Donnell, C.J. (Christopher), Taylor, K.D. (Kent), Liu, K.Y., Bottinger, E.P. (Erwin), Gottesman, R.F. (Rebecca), Daw, E.W. (E. Warwick), Giulianini, F. (Franco), Ganesh, S.K. (Santhi), Salfati, E. (Elias), Harris, T.B. (Tamara), Launer, L.J. (Lenore J.), Dörr, M. (Marcus), Felix, S.B. (Stephan), Rettig, R. (Rainer), Völzke, H. (Henry), Kim, E. (Eric), Lee, W.-J. (Wen-Jane), Lee, I.T., Sheu, W.H.-H. (Wayne H.-H.), Tsosie, K.S. (Krystal S.), Edwards, D.R.V. (Digna R. Velez), Liu, Y. (YongMei), Correa, A. (Adolfo), Weir, D.R. (David), Völker, U. (Uwe), Ridker, P.M. (Paul), Boerwinkle, E.A. (Eric), Gudnason, V. (Vilmundur), Reiner, A. (Alexander), Van Duijn, C.M. (Cornelia M.), Borecki, I.B. (Ingrid), Edwards, T.L. (Todd L.), Chakravarti, A. (Aravinda), Rotter, J.I. (Jerome I.), Psaty, B.M. (Bruce), Loos, R.J.F. (Ruth), Fornage, M. (Myriam), Ehret, G.B. (Georg), Newton-Cheh, C. (Christopher), Levy, D. (Daniel), and Chasman, D.I. (Daniel)

Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Published
2016
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7. Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

Author

Emdin, C.A. (Connor A.), Khera, A.V. (Amit V.), Natarajan, P. (Pradeep), Klarin, D. (Derek), Won, H.-H. (Hong-Hee), Peloso, G.M. (Gina), Stitziel, N.O. (Nathan), Nomura, A. (Akihiro), Zekavat, S.M. (Seyedeh M.), Bick, A.G. (Alexander G.), Gupta, N. (Namrata), Asselta, R. (Rosanna), Duga, S. (Stefano), Merlini, P.A. (Piera), Correa, A. (Adolfo), Kessler, T. (Thorsten), Wilson, J.F. (James), Bown, N., Hall, A.S. (Alistair), Braund, P.S. (Peter), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Marrugat, J. (Jaume), Elosua, R. (Roberto), McPherson, R. (Ruth), Farrall, M. (Martin), Watkins, H. (Hugh), Willer, C.J. (Cristen), Abecasis, G.R. (Gonçalo), Felix, J.F. (Janine), Vasan, R. (Ramachandran), Lander, E.S. (Eric), Rader, D.J. (Daniel), Danesh, J. (John), Ardissino, D. (Diego), Gabriel, S.B. (Stacey), Saleheen, D. (Danish), Kathiresan, S. (Sekar), Emdin, C.A. (Connor A.), Khera, A.V. (Amit V.), Natarajan, P. (Pradeep), Klarin, D. (Derek), Won, H.-H. (Hong-Hee), Peloso, G.M. (Gina), Stitziel, N.O. (Nathan), Nomura, A. (Akihiro), Zekavat, S.M. (Seyedeh M.), Bick, A.G. (Alexander G.), Gupta, N. (Namrata), Asselta, R. (Rosanna), Duga, S. (Stefano), Merlini, P.A. (Piera), Correa, A. (Adolfo), Kessler, T. (Thorsten), Wilson, J.F. (James), Bown, N., Hall, A.S. (Alistair), Braund, P.S. (Peter), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Marrugat, J. (Jaume), Elosua, R. (Roberto), McPherson, R. (Ruth), Farrall, M. (Martin), Watkins, H. (Hugh), Willer, C.J. (Cristen), Abecasis, G.R. (Gonçalo), Felix, J.F. (Janine), Vasan, R. (Ramachandran), Lander, E.S. (Eric), Rader, D.J. (Daniel), Danesh, J. (John), Ardissino, D. (Diego), Gabriel, S.B. (Stacey), Saleheen, D. (Danish), and Kathiresan, S. (Sekar)

Abstract

Background Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation. Objectives The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD. Methods We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. Results One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that

Published
2016
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8. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Author

Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), Li, M. (Mingyao), Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), and Li, M. (Mingyao)

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121-], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Published
2014
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