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1.  Impaired exercise capacity following atrial septal defect closure: an invasive study of the right heart and pulmonary circulation 
Pulmonary Circulation  2014;4(4):630-637.
Patients with early repair of an isolated atrial septal defect (ASD) are expected to have unremarkable right ventricular (RV) and pulmonary circulation physiology. Some studies, however, suggest persistent functional impairment. We aimed to examine the role of abnormal RV and pulmonary vascular response to exercise in patients who had undergone ASD closure. Using a previously published data set, we reviewed invasive exercise cardiopulmonary testing with right-sided hemodynamic data for 12 asymptomatic patients who had undergone ASD closure. The 5 (42%) patients with impaired maximal oxygen uptake () were older and exhibited a lower peak cardiac index (5.6 ± 0.8 vs. 9.0 ± 1.2 L/min/m2; P = .005) because of abnormal stroke volume augmentation (+3.2 ± 3.9 vs. +17.4 ± 10.2 mL/m2; P = .02). While all resting hemodynamic variables were similar, patients with low tended to have abnormal total pulmonary vascular resistance change during exercise (+11% ± 41% vs. −28% ± 26%; P = .06) and had a steeper relation between mean pulmonary arterial pressure and cardiac index (5.8 ± 0.6 vs. 2.2 ± 0.1 L/min/m2; P = .02). The increase in peak mean RV power during exercise was also significantly lower in the impaired- patients (4.7 ± 1.6 vs. 7.6 ± 2.1 J/s; P = .04). As described in the original study, despite normal resting hemodynamics, a subset of asymptomatic patients with repaired ASD had diminished exercise capacity. Our analysis allows us to conclude that this is due to a combination of abnormal pulmonary vascular response to exercise and impaired RV function.
doi:10.1086/678509
PMCID: PMC4278623  PMID: 25610599
atrial septal defect; right ventricle; pulmonary circulation; exercise
2.  Aggregate Risk Score Based on Markers of Inflammation, Cell Stress, and Coagulation Is an Independent Predictor of Adverse Cardiovascular Outcomes 
Objectives
This study sought to determine an aggregate, pathway-specific risk score for enhanced prediction of death and myocardial infarction (MI).
Background
Activation of inflammatory, coagulation, and cellular stress pathways contribute to atherosclerotic plaque rupture. We hypothesized that an aggregate risk score comprised of biomarkers involved in these different pathways—high-sensitivity C-reactive protein (CRP), fibrin degradation products (FDP), and heat shock protein 70 (HSP70) levels—would be a powerful predictor of death and MI.
Methods
Serum levels of CRP, FDP, and HSP70 were measured in 3,415 consecutive patients with suspected or confirmed coronary artery disease (CAD) undergoing cardiac catheterization. Survival analyses were performed with models adjusted for established risk factors.
Results
Median follow-up was 2.3 years. Hazard ratios (HRs) for all-cause death and MI based on cutpoints were as follows: CRP ≥3.0 mg/l, HR: 1.61; HSP70 >0.625 ng/ml, HR; 2.26; and FDP ≥1.0 μg/ml, HR: 1.62 (p < 0.0001 for all). An aggregate biomarker score between 0 and 3 was calculated based on these cutpoints. Compared with the group with a 0 score, HRs for all-cause death and MI were 1.83, 3.46, and 4.99 for those with scores of 1, 2, and 3, respectively (p for each: <0.001). Annual event rates were 16.3% for the 4.2% of patients with a score of 3 compared with 2.4% in 36.4% of patients with a score of 0. The C statistic and net reclassification improved (p < 0.0001) with the addition of the biomarker score.
Conclusions
An aggregate score based on serum levels of CRP, FDP, and HSP70 is a predictor of future risk of death and MI in patients with suspected or known CAD.
doi:10.1016/j.jacc.2013.03.072
PMCID: PMC4066955  PMID: 23665099
biomarker; C-reactive protein; fibrin degradation product; heat shock protein; myocardial infarction
3.  Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease 
PLoS Genetics  2014;10(7):e1004502.
The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.
Author Summary
Sudden death due to heart attack ranks among the top causes of death in the world, and family studies have shown that genetics has a substantial effect on heart disease risk. Recent studies suggest that multiple genetic factors each with modest effects are necessary for the development of CAD, but the genes and molecular processes involved remain poorly understood. We conducted an integrative genomics study where we used the information of gene-gene interactions to capture groups of genes that are most likely to increase heart disease risk. We not only confirmed the importance of several known CAD risk processes such as the metabolism and transport of cholesterol, immune response, and blood coagulation, but also revealed many novel processes such as neuroprotection, cell cycle, and proteolysis that were not previously implicated in CAD. In particular, we highlight several genes such as GLO1 with key regulatory roles within these processes not detected by the first wave of genetic analyses. These results highlight the value of integrating population genetic data with diverse resources that functionally annotate the human genome. Such integration facilitates the identification of novel molecular processes involved in the pathogenesis of CAD as well as potential novel targets for the development of efficacious therapeutic interventions.
doi:10.1371/journal.pgen.1004502
PMCID: PMC4102418  PMID: 25033284
4.  Discovery and Refinement of Loci Associated with Lipid Levels 
Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Do, Ron | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O’Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Ingi Eyjolfsson, Gudmundur | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Kathiresan, Sekar | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Gonçalo R.
Nature genetics  2013;45(11):10.1038/ng.2797.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
doi:10.1038/ng.2797
PMCID: PMC3838666  PMID: 24097068
5.  Common variants associated with plasma triglycerides and risk for coronary artery disease 
Do, Ron | Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Gao, Chi | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian'an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O'Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Eyjolfsson, Gudmundur Ingi | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Altshuler, David | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Goncalo R. | Daly, Mark J. | Neale, Benjamin M. | Kathiresan, Sekar
Nature genetics  2013;45(11):1345-1352.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
doi:10.1038/ng.2795
PMCID: PMC3904346  PMID: 24097064
6.  Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues 
Objective
Aging is a major risk factor for increased ischemic tissue injury. Whether collateral rarefaction and impaired remodeling contribute to this is unknown. We quantified the number and diameter of native collaterals, and their remodeling in 3-, 16-, 24-, and 31-months-old mice.
Methods and Results
Aging caused an “age-dose-dependent” greater drop in perfusion immediately after femoral artery ligation, followed by a diminished recovery of flow and increase in tissue injury. These effects were associated with a decline in collateral number, diameter and remodeling. Angiogenesis was also impaired. Mechanistically, these changes were not accompanied by reduced recruitment of T-cells or macrophages to remodeling collaterals. However, eNOS signaling was dysfunctional, as indicated by increased protein nitrosylation and less phosphorylated eNOS and VASP in collateral wall cells. The cerebral circulation exhibited a similar age-dose-dependent loss of collateral number and diameter and increased tortuosity, resulting in an increase in collateral resistance and infarct volume (e.g., 6- and 3-fold, respectively, in 24-months-old mice) after artery occlusion. This was not associated with rarefaction of similarly-sized arterioles. Collateral remodeling was also reduced.
Conclusions
Our findings demonstrate that aging causes rarefaction and insufficiency of the collateral circulation in multiple tissues, resulting in more severe ischemic tissue injury.
doi:10.1161/ATVBAHA.111.227314
PMCID: PMC3141082  PMID: 21617137
collateral vessels; aging; ischemia; arteriogenesis; angiogenesis
7.  Genetic variants influencing circulating lipid levels and risk of coronary artery disease 
Objectives
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9).
Conclusions
We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
doi:10.1161/ATVBAHA.109.201020
PMCID: PMC3891568  PMID: 20864672
lipids; lipoproteins; genetics; epidemiology
8.  Aging-Induced Collateral Dysfunction: Impaired Responsiveness of Collaterals and Susceptibility to Apoptosis via Dysfunctional eNOS signaling 
Despite positive animal studies, clinical angiogenesis trials have been disappointing, possibly due to risk factors present in humans but usually unexplored in animals. We recently demonstrated aging causes impaired collateral remodeling and collateral dropout; here, we investigate potential mechanisms responsible for these findings. Four-, 10-, and 18-month-C57BL/6J mice were subjected to femoral artery ligation; flow was measured using laser Doppler perfusion imaging. Endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS were measured in calf muscle. Apoptosis was assessed in endothelial (EC) and smooth muscle (SMC) cells isolated from young and old mice. Angiogenesis was measured using a Matrigel plug assay. Lethally irradiated young and old mice received bone marrow cells (BMC) from either young or old donors and were subjected to femoral artery ligation (FAL). BMC mobilization and homing were assessed. Flow recovery was impaired and less eNOS and phosphorylated eNOS was present in older vs. young mice (p<0.001 and p=0.015, respectively). ECs and SMCs from older mice were more sensitive to an apoptotic stimulus, but were rescued by NO-enhancing drugs. In older mice, angiogenesis (Matrigel plug assay) was impaired, as was mobilization and homing of BM progenitor cells following FAL. Although both mobilization and homing improved when older mice received BMC transplantation from young donors, flow recovery failed to improve. Aging impairs BMC mobilization and homing, collateral responsiveness to angiogenic stimuli, and increases EC and SMC susceptibility to apoptosis via dysfunctional eNOS signaling. The latter could contribute to impaired remodeling and collateral dropout. These finding identify potential obstacles to therapeutic interventions in elderly patients.
doi:10.1007/s12265-011-9280-4
PMCID: PMC3756560  PMID: 21538183
Aging; Progenitor cell; Angiogenesis; Collateral; eNOS; Apoptosis
9.  Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden 
Objectives
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Background
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
Methods
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
Results
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
Conclusions
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
doi:10.1016/j.jacc.2012.10.051
PMCID: PMC3653306  PMID: 23352782
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
10.  A new murine model of stress-induced complex atherosclerotic lesions 
Disease Models & Mechanisms  2013;6(2):323-331.
SUMMARY
The primary purpose of this investigation was to determine whether ApoE−/− mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE−/− mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability.
doi:10.1242/dmm.009977
PMCID: PMC3597015  PMID: 23324329
11.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study 
Voight, Benjamin F | Peloso, Gina M | Orho-Melander, Marju | Frikke-Schmidt, Ruth | Barbalic, Maja | Jensen, Majken K | Hindy, George | Hólm, Hilma | Ding, Eric L | Johnson, Toby | Schunkert, Heribert | Samani, Nilesh J | Clarke, Robert | Hopewell, Jemma C | Thompson, John F | Li, Mingyao | Thorleifsson, Gudmar | Newton-Cheh, Christopher | Musunuru, Kiran | Pirruccello, James P | Saleheen, Danish | Chen, Li | Stewart, Alexandre FR | Schillert, Arne | Thorsteinsdottir, Unnur | Thorgeirsson, Gudmundur | Anand, Sonia | Engert, James C | Morgan, Thomas | Spertus, John | Stoll, Monika | Berger, Klaus | Martinelli, Nicola | Girelli, Domenico | McKeown, Pascal P | Patterson, Christopher C | Epstein, Stephen E | Devaney, Joseph | Burnett, Mary-Susan | Mooser, Vincent | Ripatti, Samuli | Surakka, Ida | Nieminen, Markku S | Sinisalo, Juha | Lokki, Marja-Liisa | Perola, Markus | Havulinna, Aki | de Faire, Ulf | Gigante, Bruna | Ingelsson, Erik | Zeller, Tanja | Wild, Philipp | de Bakker, Paul I W | Klungel, Olaf H | Maitland-van der Zee, Anke-Hilse | Peters, Bas J M | de Boer, Anthonius | Grobbee, Diederick E | Kamphuisen, Pieter W | Deneer, Vera H M | Elbers, Clara C | Onland-Moret, N Charlotte | Hofker, Marten H | Wijmenga, Cisca | Verschuren, WM Monique | Boer, Jolanda MA | van der Schouw, Yvonne T | Rasheed, Asif | Frossard, Philippe | Demissie, Serkalem | Willer, Cristen | Do, Ron | Ordovas, Jose M | Abecasis, Gonçalo R | Boehnke, Michael | Mohlke, Karen L | Daly, Mark J | Guiducci, Candace | Burtt, Noël P | Surti, Aarti | Gonzalez, Elena | Purcell, Shaun | Gabriel, Stacey | Marrugat, Jaume | Peden, John | Erdmann, Jeanette | Diemert, Patrick | Willenborg, Christina | König, Inke R | Fischer, Marcus | Hengstenberg, Christian | Ziegler, Andreas | Buysschaert, Ian | Lambrechts, Diether | Van de Werf, Frans | Fox, Keith A | El Mokhtari, Nour Eddine | Rubin, Diana | Schrezenmeir, Jürgen | Schreiber, Stefan | Schäfer, Arne | Danesh, John | Blankenberg, Stefan | Roberts, Robert | McPherson, Ruth | Watkins, Hugh | Hall, Alistair S | Overvad, Kim | Rimm, Eric | Boerwinkle, Eric | Tybjaerg-Hansen, Anne | Cupples, L Adrienne | Reilly, Muredach P | Melander, Olle | Mannucci, Pier M | Ardissino, Diego | Siscovick, David | Elosua, Roberto | Stefansson, Kari | O'Donnell, Christopher J | Salomaa, Veikko | Rader, Daniel J | Peltonen, Leena | Schwartz, Stephen M | Altshuler, David | Kathiresan, Sekar
Lancet  2012;380(9841):572-580.
Summary
Background
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).
Interpretation
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
Funding
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
doi:10.1016/S0140-6736(12)60312-2
PMCID: PMC3419820  PMID: 22607825
12.  A Genome-wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease 
Wild, Philipp S | Zeller, Tanja | Schillert, Arne | Szymczak, Silke | Sinning, Christoph R | Deiseroth, Arne | Schnabel, Renate B | Lubos, Edith | Keller, Till | Eleftheriadis, Medea S | Bickel, Christoph | Rupprecht, Hans J | Wilde, Sandra | Rossmann, Heidi | Diemert, Patrick | Cupples, L Adrienne | Perret, Claire | Erdmann, Jeanette | Stark, Klaus | Kleber, Marcus E | Epstein, Stephen E | Voight, Benjamin F | Kuulasmaa, Kari | Li, Mingyao | Schäfer, Arne S | Klopp, Norman | Braund, Peter S | Sager, Hendrik B | Demissie, Serkalem | Proust, Carole | König, Inke R | Wichmann, Heinz-Erich | Reinhard, Wibke | Hoffmann, Michael M | Virtamo, Jarmo | Burnett, Mary Susan | Siscovick, David | Wiklund, Per Gunnar | Qu, Liming | El Mokthari, Nour Eddine | Thompson, John R | Peters, Annette | Smith, Albert V | Yon, Emmanuelle | Baumert, Jens | Hengstenberg, Christian | März, Winfried | Amouyel, Philippe | Devaney, Joseph | Schwartz, Stephen M | Saarela, Olli | Mehta, Nehal N | Rubin, Diana | Silander, Kaisa | Hall, Alistair S | Ferrieres, Jean | Harris, Tamara B | Melander, Olle | Kee, Frank | Hakonarson, Hakon | Schrezenmeir, Juergen | Gudnason, Vilmundur | Elosua, Roberto | Arveiler, Dominique | Evans, Alun | Rader, Daniel J | Illig, Thomas | Schreiber, Stefan | Bis, Joshua C | Altshuler, David | Kavousi, Maryam | Witteman, Jaqueline CM | Uitterlinden, Andre G | Hofman, Albert | Folsom, Aaron R | Barbalic, Maja | Boerwinkle, Eric | Kathiresan, Sekar | Reilly, Muredach P | O'Donnell, Christopher J | Samani, Nilesh J | Schunkert, Heribert | Cambien, Francois | Lackner, Karl J | Tiret, Laurence | Salomaa, Veikko | Munzel, Thomas | Ziegler, Andreas | Blankenberg, Stefan
Background
eQTL analyses are important to improve the understanding of genetic association results. Here, we performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).
Methods and Results
In a genome-wide association analysis of 2,078 CAD cases and 2,953 controls, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10-3. Subsequent in silico and wet-lab replication stages and a final meta-analysis of 21,428 CAD cases and 38,361 controls revealed a novel association signal at chromosome 10q23.31 within the LIPA (Lysosomal Acid Lipase A) gene (P=3.7×10-8; OR 1.1; 95% CI: 1.07-1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1,494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10-96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10-3).
Conclusions
The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which itself was related to endothelial dysfunction, a precursor of CAD.
doi:10.1161/CIRCGENETICS.110.958728
PMCID: PMC3157552  PMID: 21606135
coronary artery disease; genome-wide association studies; gene expression; genetic variation; genomics; eQTL; eSNP; LIPA
13.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Background
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10-10 versus 3.2×10-7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
Conclusions
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
doi:10.1161/CIRCGENETICS.111.961243
PMCID: PMC3335297  PMID: 22319020
coronary artery disease; myocardial infarction; meta-analysis; genetics
14.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Background
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10−10 versus 3.2×10−7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
Conclusion
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
doi:10.1161/CIRCGENETICS.111.961243
PMCID: PMC3335297  PMID: 22319020
Coronary Artery Disease; Myocardial Infarction; Meta-Analysis; Genetics
15.  Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies 
Lancet  2011;377(9763):383-392.
Summary
Background
We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.
Methods
We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12 393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).
Findings
In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10−13). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10−9). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.
Interpretation
Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.
Funding
The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.
doi:10.1016/S0140-6736(10)61996-4
PMCID: PMC3297116  PMID: 21239051
16.  Lack of association between the Trp719Arg polymorphism in kinesin-like protein 6 and coronary artery disease in 19 case-control studies 
Assimes, Themistocles L | Hólm, Hilma | Kathiresan, Sekar | Reilly, Muredach P | Thorleifsson, Gudmar | Voight, Benjamin F | Erdmann, Jeanette | Willenborg, Christina | Vaidya, Dhananjay | Xie, Changchun | Patterson, Chris C | Morgan, Thomas M | Burnett, Mary Susan | Li, Mingyao | Hlatky, Mark A | Knowles, Joshua W | Thompson, John R | Absher, Devin | Iribarren, Carlos | Go, Alan | Fortmann, Stephen P | Sidney, Stephen | Risch, Neil | Tang, Hua | Myers, Richard M | Berger, Klaus | Stoll, Monika | Shah, Svati H. | Thorgeirsson, Gudmundur | Andersen, Karl | Havulinna, Aki S | Herrera, J. Enrique | Faraday, Nauder | Kim, Yoonhee | Kral, Brian G. | Mathias, Rasika | Ruczinski, Ingo | Suktitipat, Bhoom | Wilson, Alexander F | Yanek, Lisa R. | Becker, Lewis C | Linsel-Nitschke, Patrick | Lieb, Wolfgang | König, Inke R | Hengstenberg, Christian | Fischer, Marcus | Stark, Klaus | Reinhard, Wibke | Winogradow, Janina | Grassl, Martina | Grosshennig, Anika | Preuss, Michael | Eifert, Sandra | Schreiber, Stefan | Wichmann, H-Erich | Meisinger, Christa | Yee, Jean | Friedlander, Yechiel | Do, Ron | Meigs, James B | Williams, Gordon | Nathan, David M | MacRae, Calum A | Qu, Liming | Wilensky, Robert L | Matthai, William H. | Qasim, Atif N | Hakonarson, Hakon | Pichard, Augusto D | Kent, Kenneth M | Satler, Lowell | Lindsay, Joseph M | Waksman, Ron | Knouff, Christopher W | Waterworth, Dawn M | Walker, Max C | Mooser, Vincent | Marrugat, Jaume | Lucas, Gavin | Subirana, Isaac | Sala, Joan | Ramos, Rafael | Martinelli, Nicola | Olivieri, Oliviero | Trabetti, Elisabetta | Malerba, Giovanni | Pignatti, Pier Franco | Guiducci, Candace | Mirel, Daniel | Parkin, Melissa | Hirschhorn, Joel N | Asselta, Rosanna | Duga, Stefano | Musunuru, Kiran | Daly, Mark J | Purcell, Shaun | Braund, Peter S | Wright, Benjamin J | Balmforth, Anthony J | Ball, Stephen G | Ouwehand, Willem H | Deloukas, Panos | Scholz, Michael | Cambien, Francois | Huge, Andreas | Scheffold, Thomas | Salomaa, Veikko | Girelli, Domenico | Granger, Christopher B. | Peltonen, Leena | McKeown, Pascal P | Altshuler, David | Melander, Olle | Devaney, Joseph M | Epstein, Stephen E | Rader, Daniel J | Elosua, Roberto | Engert, James C | Anand, Sonia S | Hall, Alistair S | Ziegler, Andreas | O’Donnell, Christopher J | Spertus, John A | Siscovick, David | Schwartz, Stephen M | Becker, Diane | Thorsteinsdottir, Unnur | Stefansson, Kari | Schunkert, Heribert | Samani, Nilesh J | Quertermous, Thomas
Objectives
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Background
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
Methods
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Results
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
Conclusions
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
doi:10.1016/j.jacc.2010.06.022
PMCID: PMC3084526  PMID: 20933357
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
17.  Large-scale association analyses identifies 13 new susceptibility loci for coronary artery disease 
Schunkert, Heribert | König, Inke R. | Kathiresan, Sekar | Reilly, Muredach P. | Assimes, Themistocles L. | Holm, Hilma | Preuss, Michael | Stewart, Alexandre F. R. | Barbalic, Maja | Gieger, Christian | Absher, Devin | Aherrahrou, Zouhair | Allayee, Hooman | Altshuler, David | Anand, Sonia S. | Andersen, Karl | Anderson, Jeffrey L. | Ardissino, Diego | Ball, Stephen G. | Balmforth, Anthony J. | Barnes, Timothy A. | Becker, Diane M. | Becker, Lewis C. | Berger, Klaus | Bis, Joshua C. | Boekholdt, S. Matthijs | Boerwinkle, Eric | Braund, Peter S. | Brown, Morris J. | Burnett, Mary Susan | Buysschaert, Ian | Carlquist, Cardiogenics, John F. | Chen, Li | Cichon, Sven | Codd, Veryan | Davies, Robert W. | Dedoussis, George | Dehghan, Abbas | Demissie, Serkalem | Devaney, Joseph M. | Do, Ron | Doering, Angela | Eifert, Sandra | El Mokhtari, Nour Eddine | Ellis, Stephen G. | Elosua, Roberto | Engert, James C. | Epstein, Stephen E. | Faire, Ulf de | Fischer, Marcus | Folsom, Aaron R. | Freyer, Jennifer | Gigante, Bruna | Girelli, Domenico | Gretarsdottir, Solveig | Gudnason, Vilmundur | Gulcher, Jeffrey R. | Halperin, Eran | Hammond, Naomi | Hazen, Stanley L. | Hofman, Albert | Horne, Benjamin D. | Illig, Thomas | Iribarren, Carlos | Jones, Gregory T. | Jukema, J.Wouter | Kaiser, Michael A. | Kaplan, Lee M. | Kastelein, John J.P. | Khaw, Kay-Tee | Knowles, Joshua W. | Kolovou, Genovefa | Kong, Augustine | Laaksonen, Reijo | Lambrechts, Diether | Leander, Karin | Lettre, Guillaume | Li, Mingyao | Lieb, Wolfgang | Linsel-Nitschke, Patrick | Loley, Christina | Lotery, Andrew J. | Mannucci, Pier M. | Maouche, Seraya | Martinelli, Nicola | McKeown, Pascal P. | Meisinger, Christa | Meitinger, Thomas | Melander, Olle | Merlini, Pier Angelica | Mooser, Vincent | Morgan, Thomas | Mühleisen, Thomas W. | Muhlestein, Joseph B. | Münzel, Thomas | Musunuru, Kiran | Nahrstaedt, Janja | Nelson, Christopher P. | Nöthen, Markus M. | Olivieri, Oliviero | Patel, Riyaz S. | Patterson, Chris C. | Peters, Annette | Peyvandi, Flora | Qu, Liming | Quyyumi, Arshed A. | Rader, Daniel J. | Rallidis, Loukianos S. | Rice, Catherine | Rosendaal, Frits R. | Rubin, Diana | Salomaa, Veikko | Sampietro, M. Lourdes | Sandhu, Manj S. | Schadt, Eric | Schäfer, Arne | Schillert, Arne | Schreiber, Stefan | Schrezenmeir, Jürgen | Schwartz, Stephen M. | Siscovick, David S. | Sivananthan, Mohan | Sivapalaratnam, Suthesh | Smith, Albert | Smith, Tamara B. | Snoep, Jaapjan D. | Soranzo, Nicole | Spertus, John A. | Stark, Klaus | Stirrups, Kathy | Stoll, Monika | Tang, W. H. Wilson | Tennstedt, Stephanie | Thorgeirsson, Gudmundur | Thorleifsson, Gudmar | Tomaszewski, Maciej | Uitterlinden, Andre G. | van Rij, Andre M. | Voight, Benjamin F. | Wareham, Nick J. | Wells, George A. | Wichmann, H.-Erich | Wild, Philipp S. | Willenborg, Christina | Witteman, Jaqueline C. M. | Wright, Benjamin J. | Ye, Shu | Zeller, Tanja | Ziegler, Andreas | Cambien, Francois | Goodall, Alison H. | Cupples, L. Adrienne | Quertermous, Thomas | März, Winfried | Hengstenberg, Christian | Blankenberg, Stefan | Ouwehand, Willem H. | Hall, Alistair S. | Deloukas, Panos | Thompson, John R. | Stefansson, Kari | Roberts, Robert | Thorsteinsdottir, Unnur | O’Donnell, Christopher J. | McPherson, Ruth | Erdmann, Jeanette | Samani, Nilesh J.
Nature genetics  2011;43(4):333-338.
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
doi:10.1038/ng.784
PMCID: PMC3119261  PMID: 21378990
18.  Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease 
Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.
PMCID: PMC3166154  PMID: 21915365
Epidemiology; Genetics of cardiovascular disease; Risk factors; IGF1; IGFBP3
19.  Pathway-Wide Association Study Implicates Multiple Sterol Transport and Metabolism Genes in HDL Cholesterol Regulation 
Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicate that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels.
doi:10.3389/fgene.2011.00041
PMCID: PMC3268595  PMID: 22303337
GWAS; lipid; HDL-C; pathway analysis; cholesterol; sterol transport; sterol metabolism; genetic association
20.  Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study 
Background
Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed.
Methods and Results
CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2×10−20).
Conclusion
CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.
doi:10.1161/CIRCGENETICS.109.899443
PMCID: PMC3070269  PMID: 20923989
coronary artery disease; myocardial infarction; meta-analysis; genetics
21.  A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels 
PLoS Genetics  2009;5(12):e1000768.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
Author Summary
Through a meta-analysis of genome-wide association studies of 14,733 individuals, we identified common base-pair variants in the genome which influence circulating adiponectin levels. Since adiponectin is an adipocyte-derived circulating protein which has been inversely associated with risk of obesity-related diseases such as type 2 diabetes (T2D) and coronary heart disease (CHD), we next sought to understand if the identified variants influencing adiponectin levels also influence risk of T2D, CHD, and several metabolic traits. In addition to confirming that variation at the ADIPOQ locus influences adiponectin levels, our analyses point to a variant in the ARL15 (ADP-ribosylation factor-like 15) locus which decreases adiponectin levels and increases risk of CHD and T2D. Further, this same variant was associated with increased fasting insulin levels and glycated hemoglobin. While the function of ARL15 is not known, we provide insight into the tissue specificity of ARL15 expression. These results thus provide novel insights into the physiology of the adiponectin pathway and obesity-related diseases.
doi:10.1371/journal.pgen.1000768
PMCID: PMC2781107  PMID: 20011104
22.  C-Reactive Protein, Insulin Resistance, and Metabolic Syndrome in a Population With a High Burden of Subclinical Infection 
Diabetes Care  2008;31(12):2312-2314.
OBJECTIVE—To explore relationships between C-reactive protein (CRP), subclinical infection, insulin resistance, and metabolic syndrome.
RESEARCH DESIGN AND METHODS—Data from 1,174 Eskimos, aged ≥18 years, from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study were analyzed; 40 participants with diabetes were eliminated. Baseline assessment included interviews, physical exam, and blood and urine sampling. Metabolic syndrome was assessed using Adult Treatment Panel III criteria. CRP and antibodies to common pathogens were measured.
RESULTS—Although CRP was related in univariate analyses to insulin resistance and metabolic syndrome, relations were attenuated or eliminated after adjustment for relevant covariates. CRP was not higher among those with impaired fasting glucose (IFG), and pathogen burden was not related to insulin resistance, metabolic syndrome, or IFG.
CONCLUSIONS—Pathogen burden and inflammation do not seem to be related to insulin resistance, metabolic syndrome, or IFG in this population. The inflammatory process may reflect insulin resistance or its correlates but most likely is not causative.
doi:10.2337/dc08-0815
PMCID: PMC2584187  PMID: 18796618
23.  Comparison of Nitroglycerin-, Nitroprusside-, and Phentolamine-Induced Changes in Coronary Collateral Function in Dogs 
Journal of Clinical Investigation  1977;60(2):295-301.
The recent use of vasodilators to improve ventricular function in acute myocardial infarction led us to investigate the effects of nitroglycerin, nitroprusside, and phentolamine on coronary collateral flow. Dogs were studied 2-4 wk after an ameroid constrictor was placed around the left anterior descending (LAD) coronary artery. Retrograde flow and peripheral coronary pressure were measured from a cannula inserted in the LAD distal to the ameroid. Systemic arterial pressure was held constant by an aortic cuff. When administered intracoronary (i.c.), nitroglycerin, 0.3-100 μg/min, or nitroprusside, 3-100 μg/min, produced quantitatively similar, dose-dependent increases in retrograde flow. Neither drug, i.c., changed peripheral coronary pressure. Nitroglycerin, 3-300 μg/min, intravenous (i.v.), produced dose-dependent increases in retrograde flow; nitroprusside, i.v., increased retrograde flow only in high doses (100-300 μg/min). Nitroglycerin and nitroprusside, i.v., produced similar increases in peripheral coronary pressure. Phentolamine, 1-300 μg/min, i.v., decreased retrograde flow, and did not change peripheral coronary pressure. Nitroprusside was considerably more potent than nitroglycerin in decreasing systemic arterial pressure and in reducing total coronary resistance. Thus, (a) although i.c. nitroglycerin and nitroprusside produce similar effects on collateral function, i.v. nitroglycerin is more effective than i.v. nitroprusside in augmenting collateral flow; (b) phentolamine has deleterious effects on collateral function; and (c) the relative vasodilator potencies of nitroglycerin and nitroprusside vary in different vascular beds; thus, for a given reduction in systemic arterial pressure, nitroprusside is less effective in increasing retrograde flow.
PMCID: PMC372369  PMID: 406277
24.  Potentiation of the contractile effects of norepinephrine by hypoxia 
Journal of Clinical Investigation  1972;51(9):2459-2464.
Hypoxia has been found to depress the concentration response curve of norepinephrine (NE) in isoalted cat papillary muscles. To investigate the effects of hypoxia in intact hearts, a heart-lung preparation was developed and maximum left ventricular dp/dt (max dp/dt) was measured at constant heart rate, preload, and after load. Left main coronary arterial flow (Qe) was measured with an electromagnetic flow probe. As arterial PO2 decreased from 90 mm Hg (96% saturation) to 20-25 mm Hg (40% saturation) at constant PCO2 and pH, no change in max dp/dt occurred and Qe increased 298%. In contrast to cat papillary muscles, the contractile responses to NE were augmented in hypoxia. The NE dose-response curves shifted to the left. No deterioration of contractility occurred after exposure to NE. In contrast, the chronotropic response was unaltered in hypoxia. Dose-response curves to isoproterenol also were shifted to the left in hypoxia, but responses to paired pacing were unchanged. The responses to NE under oxygenated conditions were unaltered by mechanically increased coronary flow or by increased coronary flow with nitroglycerin. Although the mechanisms responsible for these effects are unknown, the results suggest that hypoxia may open previously nonfunctioning vascular channels and thereby allow more extensive exposure of beta adrenergic receptors to circulating catecholamines.
Images
PMCID: PMC292414  PMID: 4629439
25.  Atrial fibrillation in patients with idiopathic hypertrophic subaortic stenosis 
British Heart Journal  1970;32(5):652-659.
Atrial fibrillation occurred in 16 (10%) of 167 patients with idiopathic hypertrophic subaortic stenosis. The clinical and haemodynamic findings in these 16 patients are presented.
Atrial fibrillation appeared late in the course of the disease, and its occurrence did not seem to be related to the severity of left ventricular outflow obstruction or to the amount of associated mitral regurgitation. In each patient the onset of the arrhythmia was accompanied by severe clinical deterioration, which often necessitated urgent medical treatment. Digitalis was administered to all 16 patients with subsequent clinical improvement in 15. Electrical cardioversion was uniformly successful in restoring sinus rhythm, but atrial fibrillation usually recurred. In each of 8 patients catheterized during atrial fibrillation, cardiac output was strikingly low (average, 1.9 l./min./m.2), whereas it was normal in 10 of 13 patients studied in sinus rhythm. The duration of follow-up from the onset of atrial fibrillation has averaged 5 years, and 3 of the 16 patients have died of causes related to their heart disease. Four have suffered cerebral emboli. Only 5 patients are now in stable sinus rhythm; in general, they are less symptomatic than the patients in whom atrial fibrillation has recurred.
The unusually severe clinical deterioration at the onset of atrial fibrillation and the low cardiac output measured during catheterization are thought to be related to the loss of the important contribution to ventricular filling of atrial systole in patients with poorly compliant ventricles, and to the effect of an irregular ventricular rhythm on the variable nature of the outflow obstruction.
Images
PMCID: PMC487387  PMID: 5528380

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