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Smoking, atherosclerosis and MCSF gene variations

Institution: University of Southern California
Investigator(s): Maura Paul-Labrador, MPH
Award Cycle: 2004 (Cycle 13) Grant #: 13DT-0006 Award: $57,480
Subject Area: Cardiovascular Disease
Award Type: Dissertation Awards

Initial Award Abstract
Cigarette smoking is a widely recognized risk factor for cardiovascular disease (CVD). Atherosclerosis, the formation of lesions in blood vessel walls, is an underlying process in the development of CVD. One important component in the development of atherosclerosis is Macrophage Colony Stimulating Factor (MCSF), a growth factor that activates specific immune cells called monocytes. Activated monocytes enter blood vessel walls and cause an inflammatory response that leads to thickening and remodeling of vessel walls and may ultimately result in atherosclerosis. In fact, MCSF is so important to the process of atherosclerosis, that in mice unable to produce MCSF as a result of a genetic mutation, little or no atherosclerosis occurs.

A genetic variation of the MCSF gene exists in humans and appears to substantially increase atherosclerosis risk among smokers. Atherosclerosis measurement was determined by a non-invasive ultrasound procedure that measures the thickness of blood vessel walls. Increased wall thickness is an indicator of early atherosclerosis. Preliminary data from our ongoing observational study, the Los Angeles Atherosclerosis Study, suggest that among people with the variant MCSF gene, current smokers experience about 300% more atherosclerotic progression (worsening) than never smokers. Among smokers with the variant gene who quit smoking, atherosclerosis regressed (improved) by 200%. Conversely, among people with the normal gene, atherosclerotic progression increased by 30% in current smokers and 10% in former smokers, compared to never smokers.

We have hypothesized a mechanism to explain the increased atherosclerotic progression observed among current smokers who have the variant MCSF gene. Briefly, we hypothesize that in response to vessel damage caused by smoking, the variant gene produces excessive amounts of MCSF which increase the numbers of activated monocytes migrating to vessel walls. This causes increased remodeling and thickening of the blood vessel walls, ultimately leading to more atherosclerosis than observed among people with the normal MCSF gene. This hypothesis may also explain the regression observed among former smokers who have the variant gene, since presumably, less MCSF would be produced, thereby reducing the amount of inflammation and thickness of the blood vessel wall.

We propose to confirm our preliminary results of increased atherosclerotic progression among smokers with the variant MCSF gene by performing additional statistical tests. We also plan to test our hypothesized mechanism by running experiments to determine if the variant genes of smokers produce more MCSF than normal genes of smokers. We will also explore the impact of two different genetic variations of the MCSF gene on smoking-related atherosclerosis, and attempt to replicate all of our findings using data and genetic samples from another study population.

To our knowledge, this will be the first study to 1) link a variant MCSF gene to smoking-related atherosclerosis, and 2) investigate a mechanism by which smoking increases atherosclerosis. Answers to these questions may have important implications for the identification of a group of smokers at increased risk for cardiovascular disease who may benefit the most from smoking cessation programs. Further, better understanding of the role of MCSF gene variations among smokers and non-smokers could lead to new treatment strategies for the prevention and treatment of cardiovascular disease.