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Contribution of multiple genetic variants, identified in genome-wide association studies, to coronary artery disease in HIV-infected individuals

Applicant Tarr Philip Edward
Number 127631
Funding scheme Project funding (special)
Research institution Kantonsspital Bruderholz
Institution of higher education University of Basel - BS
Main discipline Internal Medicine
Start/End 01.12.2009 - 31.12.2011
Approved amount 104'166.00
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Keywords (12)

Coronary Artery Disease; HIV Infection; Single Nucleotide Polymorphisms; Pharmacogenomics; Antiretroviral Therapy; HIV; myocardial infarction; genetics; case control study; genome wide association study; large nested project; Swiss HIV Cohort Study

Lay Summary (English)

Lead
Lay summary
Ever since the availability of highly active combinations of anti-HIV medications (antiretroviral therapy or ART) in 1995, HIV-infected individuals have a dramatically improved quality of life and prolonged life expectancy. However, new health concerns have emerged in HIV-infected persons, including an increased risk of so-called "metabolic" complications, which include cholesterol problems, high blood pressure, diabetes and, most concerning, an increased risk of heart attack at a premature age. This increased heart attack risk has been attributed to a number of factors, including the fact that HIV-infected persons smoke more, and certain ART medications which increase the heart attack risk by increasing the level of "bad" cholesterol and other mechanisms. In addition, it has long been known that the risk of having a heart attack is approx. 50% hereditary, i.e. a genetic predisposition may explain 50% of the risk. However, the genes that are involved in this predisposition were not well known until 2007. That year, a number of large studies that have scanned the entire DNA (genome) of thousands of people without HIV infection (so-called genome-wide association studies) have established an inventory of >50 gene variants that are reliably linked to heart attack risk. The aim of our study is to look at these gene variants (so-called single nucleotide polymorphisms or SNPs) in HIV-infected individuals, in order to see if we can find a set of SNPs that can predict heart attack risk. We will study 2400 HIV-infected patients. Of these, 600 have had heart attacks (or heart vessel dilation and stenting or heart bypass surgery) and 1800 "control" patients who have not. To this end, an international consortium of 17 collections of HIV-infected persons (cohort studies) from Europe, the US, and Australia, has been established, the lead being taken by the Swiss HIV Cohort Study (www.shcs.ch). We will assess to what extent SNPs and known "risk factors", including smoking, cholesterol levels, etc. explain the risk of having a heart attack in these patients. Identifying a genetic predisposition to heart attack in HIV-infected patients would represent an important scientific advance. It would not only enhance our scientific understanding of the factors that lead to heart attacks, but would have important implications for the medical care of HIV-infected persons: In persons at high genetic risk of heart attack, the HIV specialist might select a different (more heart-friendly) ART combination of drugs, or might make increased efforts at getting the patient to quit smoking, at treating high blood pressure etc.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons
Rotger M., Glass T. R., Junier T., Lundgren J., Neaton J. D., Poloni E. S., van 't Wout A. B., Lubomirov R., Colombo S., Martinez R., Rauch A., Gunthard H. F., Neuhaus J., Wentworth D., van Manen D., Gras L. A., Schuitemaker H., Albini L., Torti C., Jacobson L. P., Li X., Kingsley L. A., Carli F., Guaraldi G., Tarr P.E. (2013), Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons, in Clinical Infectious Diseases, 57(1), 112-121.
Pharmacogenomics of HIV therapy: summary of a workshop sponsored by the National Institute of Allergy and Infectious Diseases.
Haas David W, Kuritzkes Daniel R, Ritchie Marylyn D, Amur Shashi, Gage Brian F, Maartens Gary, Masys Dan, Fellay Jacques, Phillips Elizabeth, Ribaudo Heather J, Freedberg Kenneth A, Petropoulos Christos, Manolio Teri A, Gulick Roy M, Haubrich Richard, Kim Peter, Dehlinger Marjorie, Abebe Rahel, Telenti Amalio, Workshop Pharmacogenomics-A Path Towards Personalized HIV Care (2011), Pharmacogenomics of HIV therapy: summary of a workshop sponsored by the National Institute of Allergy and Infectious Diseases., in HIV clinical trials, 12(5), 277-85.
Genetic screening for metabolic and age-related complications in HIV-infected persons.
Tarr Philip E, Telenti Amalio (2010), Genetic screening for metabolic and age-related complications in HIV-infected persons., in F1000 medicine reports, 2, 83-83.

Collaboration

Group / person Country
Types of collaboration
Framingham Heart Study United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Multicenter AIDS Cohort Study United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
INSIGHT (International network for strategic initiatives in global HIV trials) United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Lluita contra la Sida, Fondacion IrsiCaixa, Barcelona Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
St. Pierre HIV Cohort Study, Bruxelles Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Hospital Clinic, University of Barcelona Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University of Modena and Reggio Emilia School of Medicine Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University of Brescia School of Medicine Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University Hospital La Paz, Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Center for HIV and Hepatogastroenterology Düsseldorf Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University Hospital Bonn Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University Hospital Reus Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University Hospital Palma de Mallorca Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
ATHENA Cohort, University of Amsterdam United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
ICONA Study, Rome Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University Hospital Köln Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Tufts University School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
LATINA HIV Cohort Study, Ospidal Italiano, Buenos Aires Argentina (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Catholic University Rome Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
National Institute of Allergy and Infectious Diseases (NIAID) of the NIH United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University College Dublin Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Australian HIV Outpatient Database (AHOD) Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
INSIGHT (International network for strategic initiatives in global HIV trials) Scientific Retreat: HIV, Inflammatory and Coagulation Markers, and End Organ Disease Talk given at a conference Contribution of Genetic and Clinical Risk Factors to Acute Coronary Artery Disease Events in HIV-infected Individuals: The MAGNIFICENT Consortium 05.01.2012 Bethesda, MD, USA, United States of America Tarr Philip Edward;
Speaker “Genetic mechanisms in metabolic complications in HIV infection”, University of Geneva Infectious Diseases Unit Talk given at a conference Genetics of Metabolic Complications in HIV Infection 08.03.2011 Geneva, CH, Switzerland Tarr Philip Edward;
Grand Rounds Speaker “Genetic mechanisms in metabolic complications in HIV infection”, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health Talk given at a conference Genetic mechanisms in metabolic complications in HIV infection 04.03.2011 Bethesda, MD, USA, United States of America Tarr Philip Edward;
Plenary Speaker “HIV Host Genomics”, 2nd International congress on AIDS and Retroviruses (ICAR) Talk given at a conference Genetic Screening for HIV-related complications 22.06.2010 Brescia, Italy, Italy Tarr Philip Edward;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Speaker, AIDS Hilfe beider Basel: HIV und Älterwerden German-speaking Switzerland 2011

Awards

Title Year
INFECTIGEN 2009

Associated projects

Number Title Start Funding scheme
134277 Swiss HIV Cohort Study (SHCS) 01.01.2011 Cohort Studies Large
108787 Swiss HIV Cohort Study 01.04.2006 Cohort Studies Large
112655 Managing variability in HIV therapy: integration of pharmacogenetics, pharmacokinetics and pharmacodynamics of antiretroviral drugs 01.04.2006 Project funding (special)
144209 Dynamics of atherosclerosis progression in HIV-infected and HIV-uninfected persons - a longitudinal study using coronary computed tomography angiography 01.07.2013 Project funding (special)
69366 Swiss HIV Cohort Study 01.01.2003 Project funding (special)
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large

Abstract

Background: Large epidemiological studies suggest that HIV-infected individuals are at increased risk for premature coronary artery disease (CAD) events. The presumed mechanisms include a high prevalence of traditional risk factors for CAD, HIV-specific endothelial damage, alterations of inflammatory and pro-coagulant mechanisms, and exposure to particular antiretroviral drugs. Recent genome-wide association studies (GWAS) have convincingly associated common single nucleotide polymorphisms (SNPs) with CAD in the general population. To date, no study has investigated such SNPs in HIV-infected individuals, and no study has quantitated the relative importance of genetic and non-genetic factors in CAD in HIV-infected individuals.Aim: To evaluate the contribution of SNPs identified in GWAS and of combination antiretroviral therapy (cART), traditional CAD risk factors, and HIV-related factors (CD4+ count, HIV RNA levels) to acute CAD events in HIV-infected individuals.Design: Nested case-control study Setting: International collaborative project of 14 Observational HIV Cohort StudiesIndividuals: Cases are HIV-infected individuals with acute CAD events including myocardial infarction, acute angina pectoris, percutaneous coronary angioplasty, coronary bypass surgery, and death due to myocardial infarction, cardiac arrhythmias or congestive heart failure. Controls are HIV-infected individuals enrolled in the same cohort and matched for age and gender at the time of the case CAD event.Genetic Analysis: Participating international cohort studies have agreed to provide DNA from well-phenotyped individuals. All DNA will be extracted locally and sent for genotyping to the Institute for Microbiology/University of Lausanne. Genotyping will be done using the Veracode technology (Illumina).Variables: The following variables will be collected from all participants: Age, gender, ethnicity, complete antiretroviral history, smoking status, family history of premature CAD, history of diabetes mellitus, blood glucose, blood pressure, total cholesterol, HDL, non-HDL cholesterol, triglycerides, treatment history for dyslipidemia, hypertension and diabetes, hepatitis C antibodies, HIV transmission category, CD4+ count, HIV viral load. Data management: Data management will be done at the University of Lausanne with support and surveillance by the Basel Institute for Clinical Epidemiology and Biostatistics (BICE) that will be responsible for data analysis. Goals: 1.Evaluation of the individual and cumulative impact (CAD-protective or CAD-permissive) of 45 SNPs, identified in GWAS, on CAD events in HIV-infected individuals from 14 international observational cohort studies.2.Calculation of the percent variance in CAD risk explained by genetic and non-genetic factors, including, most notably, cART, traditional CAD risk factors, and HIV-related factors (CD4+ count, HIV RNA levels). Sample size and data analysis: 552 individuals with a first acute CAD event (n=159 enrolled in SHCS and n=393 in international cohort studies), that will be matched to 1815 randomly selected, HIV-infected control individuals without CAD (of which 636 SHCS controls + 1179 non-SHCS controls), for a total study population of 2367 individuals. Matching for cases will be stratified at each individual cohort level. Data analysis will include determination of allelic frequencies of each SNP in cases and controls. Conditional logistic regression stratified by case-control stratum will be used to estimate the odds ratios of an acute CAD event for each SNP adjusted for non-genetic variables and percent variance explained by genetic/non-genetic variables. Multi-variable regression models including genetic and non-genetic variables for prediction of acute CAD events will be assessed. Significance: Identification of genetic factors that contribute to the cardiovascular risk and clarifying the relative importance of genetic, antiretroviral, and other key non-genetic factors would be of major importance for CAD risk stratification in HIV-infected individuals.
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