ABSTRACT
OBJECTIVE: Genetic variation in coagulation and fibrinolysis may affect the development of subclinical atherosclerosis modifying the risk of stroke and cardiovascular disease. However, data on the relationship between subclinical atherosclerosis and genes involved in the coagulation system are sparse. The objective of this study is to examine the association between single nucleotide polymorphisms (SNPs) in coagulation system genes and subclinical carotid plaque phenotypes. METHODS: From the Genetic Determinants of Subclinical Carotid Disease Study, 287 Dominicans were examined for carotid plaque presence, thickness, and surface irregularity by high-resolution B-mode carotid ultrasound. Logistic regression was used to test for association between 101 SNPs in 23 coagulation system genes and plaque phenotypes while controlling for age, sex, smoking, hypertension, dyslipidemia, and diabetes. Within gene haplotypes and interactions between genes were examined. A follow-up of SNPs in moderate to high (r(2)>0.25) linkage disequilibrium (LD) with those implicated in the discovery analysis (p ≤ 0.01) was performed in an independent sample of 301 Dominicans. RESULTS: The prevalence of carotid plaque (47% discovery; 46% follow-up) as well as the mean age (65 ± 8 discovery; 65 ± 9 follow-up) of the participants was similar in both datasets. Two genes (vWF and THBS1) were associated (p ≤ 0.01) with plaque size and surface irregularity. In follow-up, 5 SNPs in vWF were associated (p ≤ 0.05) with plaque size. SERPINE1 was an additional gene of interest in the haplotype and interaction analyses. CONCLUSIONS: Variation in the vWF, THBS1, and SERPINE1 gene may play an important role in the pathogenesis of atherosclerotic plaque.
Subject(s)
Blood Coagulation/genetics , Carotid Artery Diseases/genetics , Plaque, Atherosclerotic/genetics , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Single Nucleotide , Thrombospondin 1/genetics , von Willebrand Factor/genetics , Age of Onset , Aged , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/epidemiology , Comorbidity , Diabetes Mellitus/epidemiology , Dominican Republic/ethnology , Dyslipidemias/epidemiology , Epistasis, Genetic/genetics , Female , Follow-Up Studies , Genetic Association Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , Haplotypes , Humans , Hypertension/epidemiology , Logistic Models , Male , Middle Aged , New York City/epidemiology , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/epidemiology , Plasminogen Activator Inhibitor 1/physiology , Prevalence , Prospective Studies , Risk Factors , Smoking/epidemiology , Thrombospondin 1/physiology , Ultrasonography , von Willebrand Factor/physiologyABSTRACT
Obesity is a well-known risk factor for the development of insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. Rather than the total amount of fat, central distribution of adipose tissue is very important in the pathophysiology of this constellation of abnormalities termed metabolic syndrome. Adipose tissue, regarded only as an energy storage organ until the last decade, is now known as the biggest endocrine organ of the human body. This tissue secretes a number of substances--adipocytokines--with multiple functions in metabolic profile and immunological process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as CVD. Adipocytokines may act locally or distally as inflammatory, immune or hormonal signalers. In this review we discuss visceral obesity, the potential mechanisms by which it would be related to insulin resistance, methods for its assessment and focus on the main adipocytokines expressed and secreted by the adipose tissue. Particularly, we review the role of adiponectin, leptin, resistin, angiotensinogen, TNF-alpha, and PAI-1, describing their impact on insulin resistance and cardiovascular risk, based on more recent findings in this area.