Association between a leukotriene C4 synthase gene promoter polymorphism and coronary artery calcium in young women: the Muscatine Study.
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.


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.
Iovannisci
David M
DM
Childrens's Hospital and Research Center Oakland, CA, USA. Diovannisci@chori.org
Lammer
Edward J
EJ
Steiner
Lori
L
Cheng
Suzanne
S
Mahoney
Larry T
LT
Davis
Patricia H
PH
Lauer
Ronald M
RM
Burns
Trudy L
TL
D000328:Adult; D000367:Age Factors; D001161:Arteriosclerosis / Q000201:enzymology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002318:Cardiovascular Diseases; D003331:Coronary Vessels / Q000201:enzymology*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D015289:Leukotrienes / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D017539:Tunica Intima / Q000473:pathology; D015854:Up-Regulation
D015289:Leukotrienes; D012333:RNA, Messenger; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D002118:Calcium