Tissue factor gene promoter haplotype associates with carotid intima-media thickness in subjects in cardiovascular risk prevention.
OBJECTIVE
Tissue factor (TF), key initiator of coagulation, has been ascribed roles not only in thrombosis but also in atherosclerosis. TF gene promoter haplotypes modulate TF expression, thereby potentially affecting atherosclerosis. The objective of this study was to evaluate functionally relevant TF promoter haplotypes as determinants of carotid intima-media thickness (C-IMT), a marker of atherosclerosis.


METHODS
The haplotype-tagging TF A-603G polymorphism and C-IMT were determined in 611 subjects referred to cardiovascular risk prevention. Subjects were aged 59.7 (58.1-61.1) years (mean (95% C.I.)), 79% were male, and 74% in secondary prevention with a history of coronary, cerebrovascular, or peripheral atherosclerotic disease. TF plasma levels were measured in 120 subjects.


RESULTS
Significant dose-dependent associations were found between A-603G genotype and both IMT(max) and IMT(mean-max) after adjusting for potential confounders. IMT values were highest in A/A (n=173), intermediate in A/G (n=312) and lowest in G/G (n=126). IMT(max) values (average and 95% C.I., in mm) for A/A, A/G and G/G, were 2.22 (2.11-2.34), 2.09 (2.01-2.18) and 2.02 (1.90-2.15), respectively (p(trend)=0.019), and IMT(mean-max) values were 1.28 (1.23-1.32), 1.25 (1.22-1.28) and 1.21 (1.16-1.26), respectively (p(trend)=0.041). A significant interaction between A-603G genotype and prevention status was found (p=0.046 and p=0.042 for IMT(max) and IMT(mean-max), respectively). TF plasma levels did not differ between genotypes and were not determinants of C-IMT.


CONCLUSIONS
The haplotype-tagging TF A-603G polymorphism is associated with C-IMT, independently of TF levels in plasma. These findings provide clinical evidence of an involvement of TF in atherosclerosis, in addition to its well-known roles in hemostasis and thrombosis.
Gertow
Karl
K
Centro Cardiologico Monzino, Via Parea 4, 20138 Milan, Italy. karl.gertow@yahoo.com
Amato
Mauro
M
Werba
José Pablo
JP
Bianchi
Elena
E
Parolari
Alessandro
A
Colnago
Deborah
D
Brambilla
Marta
M
Ravani
Alessio
A
Veglia
Fabrizio
F
Baldassarre
Damiano
D
Camera
Marina
M
Tremoli
Elena
E
D002318:Cardiovascular Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000517:prevention & control*; D002339:Carotid Arteries / Q000000981:diagnostic imaging*; D002340:Carotid Artery Diseases / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D055502:Secondary Prevention; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism; D017539:Tunica Intima / Q000000981:diagnostic imaging*; D017540:Tunica Media / Q000000981:diagnostic imaging*; D014463:Ultrasonography
D013925:Thromboplastin