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Gene-by-Smoking Interactions and Risk of Atherosclerosis - Ancillary to ARIC

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00064545
Recruitment Status : Completed
First Posted : July 10, 2003
Last Update Posted : December 13, 2012
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Kari North, PhD, University of North Carolina, Chapel Hill

Brief Summary:
To evaluate common genetic variations, that in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis.

Condition or disease
Atherosclerosis Cardiovascular Diseases Heart Diseases Coronary Disease Carotid Artery Diseases Peripheral Vascular Diseases Cerebral Arteriosclerosis Cerebrovascular Accident

Detailed Description:


While cigarette smoking is a well-established and potent risk factor for atherosclerotic vascular disease, individual susceptibility to smoking varies considerably, suggesting modifiers such as genomic variation. Several key enzymes involved in the activation and detoxification of mutagenic tobacco smoke compounds, oxidative stress, and DNA damage are expressed in the tissues of the heart and vasculature and represent mechanistic pathways for tobacco-induced pathology. Many of these enzymes have common polymorphisms (greater than or equal too 10% prevalence in the population) with known functional effects. Although restricted to a few enzymes and hampered by shortcomings in design, a small number of studies have suggested that enzymatic activation and detoxification of tobacco smoke modifies the risk of certain cardiovascular outcomes associated with cigarette smoking.


The genetic epidemiology study will evaluate common genetic polymorphisms that, in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis and its clinical sequelae. An average of six polymorphisms, selected on the basis of their prevalence and functional significance, expression in relevant tissues, evaluation in previous studies and biologic plausibility, within 19 genes involved in activation, detoxification, oxidative stress, and DNA repair pathways will be evaluated as an ancillary study to the Atherosclerosis Risk in Communities (ARIC) study. In this well-characterized, bi-ethnic cohort of 15,792 men and women under active follow-up since 1987-89 (completeness of follow-up 96%), five endpoints quantifying subclinical atherosclerosis and validated clinical atherosclerotic events will be studied in case-cohort/case-control mode: incident coronary heart disease, carotid atherosclerosis, peripheral arterial disease, incident stroke, and MRI-detected cerebral infarcts. The study is well designed to study how DNA sequence polymorphisms can promote or inhibit the atherogenic effects of smoking and the risk of clinical events, and to contribute new knowledge on the role of genetic variation in the response to environmental insults and toxicants.

A case-cohort or case-control approach will be taken, using data from the Atherosclerosis Risk in Communities (ARIC) study. Approximately 20 polymorphisms will be examined in relation to five cardiovascular disease (CVD) endpoints. The polymorphisms to be examined are classified as variants of either a) Phase I (activation) enzymes, b) Phase II (detoxification) enzymes, c) oxidative stress enzymes, or d) DNA repair enzymes. The CVD endpoints include incident coronary heart disease (CHD) cases (n=1,101), incident stroke cases (n=323), prevalent peripheral artery disease (PAD) (n=237 cases), carotid atherosclerosis determined by MRI (n=504 cases), and cerebral infarcts (n=237cases). Controls will consist of 1,062 controls selected at visit 1, and 237 visit-3 controls for the cerebral infarct cases. The statistical approach will be based on the proportional hazards regression for incident CHD and stroke endpoints, and logistic regression for the other CVD outcomes. Both additive and multiplicative forms of interaction will be tested.

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Study Type : Observational
Actual Enrollment : 1500 participants
Observational Model: Case Control
Study Start Date : July 2003
Actual Primary Completion Date : June 2008
Actual Study Completion Date : June 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis

Primary Outcome Measures :
  1. CHD [ Time Frame: Baseline - 2001 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
ARIC cohort, incident cases of CHD and cohort representative sample.
No eligibility criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00064545

Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Kari North University of North Carolina, Chapel Hill
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Responsible Party: Kari North, PhD, Associate Professor, University of North Carolina, Chapel Hill Identifier: NCT00064545    
Other Study ID Numbers: 1227
5R01HL074377 ( U.S. NIH Grant/Contract )
First Posted: July 10, 2003    Key Record Dates
Last Update Posted: December 13, 2012
Last Verified: December 2012
Additional relevant MeSH terms:
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Carotid Artery Diseases
Intracranial Arteriosclerosis
Heart Diseases
Vascular Diseases
Coronary Disease
Peripheral Vascular Diseases
Peripheral Arterial Disease
Cardiovascular Diseases
Arterial Occlusive Diseases
Myocardial Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Intracranial Arterial Diseases