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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00064545
Other study ID # 1227
Secondary ID 5R01HL074377
Status Completed
Phase N/A
First received July 8, 2003
Last updated December 11, 2012
Start date July 2003
Est. completion date June 2008

Study information

Verified date December 2012
Source University of North Carolina, Chapel Hill
Contact n/a
Is FDA regulated No
Health authority United States: Federal Government
Study type Observational

Clinical Trial Summary

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


Description:

BACKGROUND:

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.

DESIGN NARRATIVE:

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.


Recruitment information / eligibility

Status Completed
Enrollment 1500
Est. completion date June 2008
Est. primary completion date June 2008
Accepts healthy volunteers No
Gender Both
Age group N/A and older
Eligibility No eligibility criteria

Study Design

Observational Model: Case Control


Locations

Country Name City State
n/a

Sponsors (2)

Lead Sponsor Collaborator
University of North Carolina, Chapel Hill National Heart, Lung, and Blood Institute (NHLBI)

Outcome

Type Measure Description Time frame Safety issue
Primary CHD Baseline - 2001 No
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