Article

Polymorphism in the cholesteryl ester transfer protein gene and the risk of early onset myocardial infarction among cigarette smokers

Division of General Medicine, University of Rochester, Rochester, New York, United States
Annals of Noninvasive Electrocardiology (Impact Factor: 1.44). 10/2007; 12(4):364-74. DOI: 10.1111/j.1542-474X.2007.00186.x
Source: PubMed

ABSTRACT Cigarette smoking and the common B1 allele of the TaqIB polymorphism have both been reported to be associated with increased cholesteryl ester transfer protein (CETP) activity and altered lipoprotein levels. Thus, it is possible that the combined presence of these two respective environmental and genetic factors may enhance cardiovascular risk. We hypothesized that susceptibility to early onset myocardial infarction (MI) among cigarette smokers may be related to the presence of TaqIB polymorphism in the CETP gene.
The age at onset of a first MI among current (n = 199), past (n = 345), and never (n = 270) smokers was related to the presence of the TaqIB1 and B2 alleles in a cohort of 814 first MI patients.
Multivariate regression analysis demonstrated that cigarette smoking was associated with a significant increase in the risk for early onset MI only among carriers of the TaqIB1 allele: current smokers with the B1B1 and B1B2 genotypes displayed a respective 9.4 (P < 0.001) and 8.4 (P < 0.001) year reduction in the age at onset of a first MI compared with never smokers, and past smokers with these genotypes exhibited a respective 3.8 (P = 0.003) and 3.7 (P = 0.01) year reduction. By contrast, current and past smoking was not associated with a significant increase in the risk for early onset MI among B2B2 homozygotes (3.0 [P = 0.28] and 0.2 [P = 0.93] year reduction, respectively). The smoking x genotype interaction was statistically significant (P = 0.04).
The current findings suggest that genetic factors may modify susceptibility to early onset MI among cigarette smokers.

0 Followers
 · 
84 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this work was to investigate whether fibrinolysis plays a role in establishing recurrent coronary event risk in a previously identified group of postinfarction patients. This group of patients was defined as having concurrently high levels of high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) and was previously demonstrated to be at high-risk for recurrent coronary events. Potential risk associations of a genetic polymorphism of plasminogen activator inhibitor-2 (PAI-2) were probed as well as potential modulatory effects on such risk of a polymorphism of low-density lipoprotein receptor related protein (LRP-1), a scavenger receptor known to be involved in fibrinolysis in the context of cellular internalization of plasminogen activator/plansminogen activator inhibitor complexes. To this end, Cox multivariable modeling was performed as a function of genetic polymorphisms of PAI-2 (SERPINB, rs6095) and LRP-1 (LRP1, rs1800156) as well as a set of clinical parameters, blood biomarkers, and genetic polymorphisms previously demonstrated to be significantly and independently associated with risk in the study population including cholesteryl ester transfer protein (CETP, rs708272), p22phox (CYBA, rs4673), and thrombospondin-4 (THBS4, rs1866389). Risk association was demonstrated for the reference allele of the PAI-2 polymorphism (hazard ratio 0.41 per allele, 95% CI 0.20-0.84, p=0.014) along with continued significant risk associations for the p22phox and thrombospondin-4 polymorphisms. Additionally, further analysis revealed interaction of the LRP-1 and PAI-2 polymorphisms in generating differential risk that was illustrated using Kaplan-Meier survival analysis. We conclude from the study that fibrinolysis likely plays a role in establishing recurrent coronary risk in postinfarction patients with concurrently high levels of HDL-C and CRP as manifested by differential effects on risk by polymorphisms of several genes linked to key actions involved in the fibrinolytic process.
    PLoS ONE 07/2013; 8(7):e68920. DOI:10.1371/journal.pone.0068920 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Few studies are available in human populations investigating involvement of vascular inflammation and oxidative stress-related dysfunctional transformation of high-density lipoprotein (HDL) in establishing cardiovascular disease (CVD) risk. To this end, the current work investigated a subgroup of post-infarction patients at high-risk for recurrent events defined by high levels of HDL cholesterol (HDL-C) and concurrently high levels of C-reactive protein (CRP). Thrombospondin-4 (TSP-4), a matricellular protein of vessel walls associated with inflammation, was investigated in terms of CVD risk using multivariable modelling with a well-characterised functional genetic polymorphism of THBS4 (A387P, rs1866389) along with previously demonstrated risk-related functional genetic polymorphisms of CYBA (C242T, rs4673) and CETP (TaqIB, rs708272), and a set of blood markers. Results revealed risk-association for the gain-of-function P-allele of the THBS4 polymorphism (hazard ratio 2.00, 95% confidence interval 1.10-3.65, p=0.024). Additionally, von Willebrand factor was associated with D-dimer levels in the higher-risk P allele patients suggestive of a connection between endothelial dysfunction and thrombogenesis. In conclusion, TSP-4, a matricellular protein involved in regulating vascular inflammation, plays a role in establishing recurrent coronary risk in post-infarction patients with high levels of HDL-C and CRP. Further studies should focus on additional effects of vascular inflammatory processes on anti-atherogenic functionality of HDL particles.
    Thrombosis and Haemostasis 12/2011; 106(6):1170-8. DOI:10.1160/TH11-03-0206 · 5.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Until now, there has been limited information on the effects of smoking on atherogenesis and senescence in the context of lipoprotein parameters, particularly in young smokers who have smoked fewer than 10 cigarettes per day for 3 years. In this study, lipoprotein profiles and functions were compared between smoker (n = 21) and control groups (n = 20). In the smoking group, ferric ion reduction abilities of serum and high-density lipoprotein (HDL) fractions were significantly reduced, and low-density lipoprotein (LDL) was severely oxidized. All lipoprotein particles from the smoker group showed higher advanced glycated end products with more triglyceride (TG) content compared to the control group. Lipoproteins from smokers showed faster agarose gel electromobility as well as greater smear band intensity in SDS-PAGE due to oxidation and glycation. LDL from smokers was more sensitive to oxidation and promoted foam cell forma-tion in macrophages. Gel filtration column chromatography revealed that the protein and cholesterol peaks of VLDL and LDL were elevated in the smoker group, whereas those of HDL were reduced. Human dermal fibroblast cells from the smoker group showed severe senescence following treatment with HDL2 and HDL3. Although HDL from young smokers showed impaired antioxidant ability, smaller particle size, and increased TG content, cholesteryl ester transfer protein activities were greatly enhanced in the serum and HDL fractions of the smoker group.In conclusion, smoking can cause production of dysfunctional lipoproteins having a smaller particle size that exacerbate senescence and atherogenic progress due to oxidation and glycation.
    Toxicological Sciences 05/2014; 140(1). DOI:10.1093/toxsci/kfu076 · 4.48 Impact Factor