on November 16, 2006
Published online before print November 16, 2006, doi: 10.1161/01.ATV.0000252680.72734.10
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Submitted on March 1, 2006
Accepted on October 19, 2006
Association Between A Leukotriene C4 Synthase Gene Promoter Polymorphism and Coronary Artery Calcium in Young Women. The Muscatine Study
David M. Iovannisci *;
From the Childrens’s Hospital and Research Center (D.M.I., E.J.L.), Oakland, Calif; Roche Molecular Systems (L.S., S.C.), Alameda Calif; and the Departments of Pediatrics (L.T.C., R.M.L., T.L.B.) and Neurology (P.H.D.), Carver College of Medicine, and Public Health Genetics (T.L.B.) and Epidemiology (L.T.M., R.M.L., T.L.B.), College of Public Health, The University of Iowa, Iowa City.
* To whom correspondence should be addressed. E-mail: Diovannisci{at}chori.org.
Objective--A majority of the recognized risk factors for atherosclerosis and the development of cardiovascular disease have been derived from the study of older populations who have already manifested clinical symptoms. If risk factors can be identified earlier in life, such as genetic variation, preventive measures may be taken before overt symptoms of pathology have manifested, and when treatments may be most effective.
Methods and Results--In an effort to identify individuals at increased risk for cardiovascular disease, we genotyped 732 members of the Muscatine Study Longitudinal Adult Cohort for candidate genetic markers associated with several pathogenetic processes. We identified age-adjusted increased risks for coronary artery calcium (OR 4.29; 95% CI 1.78, 10.31) and increased mean carotid artery intimal-medial thickness associated with the (-444)A>C promoter polymorphism of Leukotriene C4 Synthase (LTC4S) in women. There were no similar associations in men.
Conclusions--LTC4S plays a key role in the process of inflammation as the rate limiting enzyme in the conversion of arachidonic acid to cysteinyl-leukotrienes, important mediators of inflammatory responses. The (-444)C variant upregulates LTC4S mRNA expression, increasing the synthesis of proinflammatory leukotrienes. Our results support genetic variation modifying inflammatory pathways as an important mechanism in the development of atherosclerosis.
Key words: atherosclerosis • epidemiology • coronary artery calcification • calcification • leukotriene
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