- Email: [email protected]
A polymorphism of the cholesterol ester transfer protein gene predicts cardiovascular events in non-smokers in the west of scotland coronary prevention study
Association of Gene Polymorphisms With Coronary Artery Disease in Low- or High-Risk Subjects Defined by Conventional Risk Factors
Study Question: Do specific gene polymorphisms of the cholesterol ester transfer protein (CETP) influence the risk of cardiovascular events (CVE), what is the impact on LDL and HDL particle size and is there a gene-smoking or gene-treatment interaction? Methods: A case-controlled study using the West of Scotland Coronary Prevention Study (WOSCOPS) of men 45– 64 years with hypercholesterolemia, who were randomized to 40 mg of pravastatin or placebo and followed for 5 years. Cases (n⫽498) were matched for age and smoking status with twice the number of controls (n⫽1108) and each was typed for five CETP polymorphisms. Cases were defined as experiencing one or more of the following during the follow-up: fatal or nonfatal MI, sudden coronary death or required CABG or PCI. Primary outcome was the ability of a specific gene variation to predict CVEs. Results: The mean age was 57 years, 55% were smokers, mean cholesterol was 270 mg/dL, HDL-C 42 mg/dL, LDL-C 190 mg/dL and mean LDL particle diameter was 26.37 nm. Homozygotes for the TaqlB2 allele (B2B2) had a 30% reduced risk of a CVE, compared to B1B1 homozygotes (p⫽0.03). Inclusion of HDL or LDL particle diameter only marginally attenuated the relationship. Non-smokers, but not smokers, showed a dose-dependent association with risk with the TaqlB genotype. Treatment benefit (pravastatin vs. placebo) was not significantly different in B1B1 (risk reduction, RR⫽0.71), B1B2 (RR⫽0.68) and B2B2 (RR⫽0.61). The other four CETP polymorphisms had no significant association with CV risk. Conclusions: The association between CETP TaqlB genotype and cardiovascular risk is primarily in non-smokers, is not fully explained by LDL and HDL particle size and the benefit of pravastatin treatment was not influenced by this polymorphism. Perspective: CETP located on HDL particles is responsible for the transfer of cholesterol from VLDL remnant to HDL particles. CETP TaqlB polymorphism is associated with HDL levels (lower with B1B1) and was associated with CHD risk in the Framingham Study but not with the risk of an MI in the Physicians Health Study. The relationship with HDL level is strongest in non-smokers and high alcohol consumption. The protective effect of the CETP B2B2 genotype was not present in smokers. So . . . smoking is bad, alcohol is probably good and, surprise, your genes don’t necessarily overcome at-risk behavior! MR
Hirashiki A, Yamada Y, Murase Y, et al. J Am Coll Cardiol 2003; 42:1429 –37. Study Question: Are there genes that confer susceptibility to coronary artery disease (CAD) and do they differ by gender and low- vs. high-risk patients. Methods: Genotypes for 37 polymorphisms of 31 candidate genes were determined in 1011 patients with CAD and 650 control subjects who were Japanese and unrelated. High risk was defined by the presence of hypertension, diabetes or hypercholesterolemia and low risk the absence of each. Candidate genes belonged to the following families: ACE, Ang II, apolipoproteins, connexin, CD-14, endothelin, glycoproteins, MTFR, cytokines and platelet receptors, thrombosis/thrombolysis. Results: Controls were significantly younger (56 vs. 63 years), and patients with CAD had a higher percentage of men (69% vs. 56%). Cholesterol averaged 180 mg/dL in low-risk and 250 mg/dL in high-risk men and women. In the 1661 subjects, 35% had one or more risk factor and there was no difference in percentage with or type of risk factors between CAD and controls. Age was a risk factor in all groups, hyperuricemia in high-risk men and low-risk women and smoking in low-risk men. Multivariate logistic regression with adjustment for age, BMI, smoking and hyperuricemia demonstrated risk associated with polymorphism of the apo E gene in lowrisk men, the stromelysin-1 gene in low-risk women, the connexin gene in high-risk men, and the apo E gene in high risk women. The effect of gene polymorphism was independent of age and conventional risk factors. Conclusions: Genotyping of these polymorphisms may prove informative for assessment of the genetic risk of CAD in low- or high-risk men or women. Perspective: Identifying single nucleotide polymorphisms (SNPs) of genes involved in atherosclerosis through lipid metabolism, thrombosis, inflammation and vascular matrix metabolism has been used to characterize genetic vs. environmental risk in several ethnic groups. As in hypertension, the contribution of SNPs is likely the tip of a huge iceberg. I suspect we may be floating on the Titanic for many years, particularly in the US with the ever increasing ethnic/racial diversity from immigration and intermarriage. MR
Comparing Symptoms of Depression and Anxiety as Predictors of Cardiac Events and Increased Health Care Consumption After Myocardial Infarction
A Polymorphism of the Cholesterol Ester Transfer Protein Gene Predicts Cardiovascular Events in Non-smokers in the West of Scotland Coronary Prevention Study
Strik JJM, Denollet J, Lousberg R, Honig A. J Am Coll Cardiol 2003;42:1801–7.
Freeman DJ, Samani NJ, Wilson V, et al., on behalf of the West of Scotland Study Group. Eur Heart J 2003;24:1833– 42.
Study Question: Do anxiety and depression effect post-MI mortality and health care resource consumption?
ACC CURRENT JOURNAL REVIEW Mar 2004
26
Study Question: Do specific gene polymorphisms of the cholesterol ester transfer protein (CETP) influence the risk of cardiovascular events (CVE), what is the impact on LDL and HDL particle size and is there a gene-smoking or gene-treatment interaction? Methods: A case-controlled study using the West of Scotland Coronary Prevention Study (WOSCOPS) of men 45– 64 years with hypercholesterolemia, who were randomized to 40 mg of pravastatin or placebo and followed for 5 years. Cases (n⫽498) were matched for age and smoking status with twice the number of controls (n⫽1108) and each was typed for five CETP polymorphisms. Cases were defined as experiencing one or more of the following during the follow-up: fatal or nonfatal MI, sudden coronary death or required CABG or PCI. Primary outcome was the ability of a specific gene variation to predict CVEs. Results: The mean age was 57 years, 55% were smokers, mean cholesterol was 270 mg/dL, HDL-C 42 mg/dL, LDL-C 190 mg/dL and mean LDL particle diameter was 26.37 nm. Homozygotes for the TaqlB2 allele (B2B2) had a 30% reduced risk of a CVE, compared to B1B1 homozygotes (p⫽0.03). Inclusion of HDL or LDL particle diameter only marginally attenuated the relationship. Non-smokers, but not smokers, showed a dose-dependent association with risk with the TaqlB genotype. Treatment benefit (pravastatin vs. placebo) was not significantly different in B1B1 (risk reduction, RR⫽0.71), B1B2 (RR⫽0.68) and B2B2 (RR⫽0.61). The other four CETP polymorphisms had no significant association with CV risk. Conclusions: The association between CETP TaqlB genotype and cardiovascular risk is primarily in non-smokers, is not fully explained by LDL and HDL particle size and the benefit of pravastatin treatment was not influenced by this polymorphism. Perspective: CETP located on HDL particles is responsible for the transfer of cholesterol from VLDL remnant to HDL particles. CETP TaqlB polymorphism is associated with HDL levels (lower with B1B1) and was associated with CHD risk in the Framingham Study but not with the risk of an MI in the Physicians Health Study. The relationship with HDL level is strongest in non-smokers and high alcohol consumption. The protective effect of the CETP B2B2 genotype was not present in smokers. So . . . smoking is bad, alcohol is probably good and, surprise, your genes don’t necessarily overcome at-risk behavior! MR
Hirashiki A, Yamada Y, Murase Y, et al. J Am Coll Cardiol 2003; 42:1429 –37. Study Question: Are there genes that confer susceptibility to coronary artery disease (CAD) and do they differ by gender and low- vs. high-risk patients. Methods: Genotypes for 37 polymorphisms of 31 candidate genes were determined in 1011 patients with CAD and 650 control subjects who were Japanese and unrelated. High risk was defined by the presence of hypertension, diabetes or hypercholesterolemia and low risk the absence of each. Candidate genes belonged to the following families: ACE, Ang II, apolipoproteins, connexin, CD-14, endothelin, glycoproteins, MTFR, cytokines and platelet receptors, thrombosis/thrombolysis. Results: Controls were significantly younger (56 vs. 63 years), and patients with CAD had a higher percentage of men (69% vs. 56%). Cholesterol averaged 180 mg/dL in low-risk and 250 mg/dL in high-risk men and women. In the 1661 subjects, 35% had one or more risk factor and there was no difference in percentage with or type of risk factors between CAD and controls. Age was a risk factor in all groups, hyperuricemia in high-risk men and low-risk women and smoking in low-risk men. Multivariate logistic regression with adjustment for age, BMI, smoking and hyperuricemia demonstrated risk associated with polymorphism of the apo E gene in lowrisk men, the stromelysin-1 gene in low-risk women, the connexin gene in high-risk men, and the apo E gene in high risk women. The effect of gene polymorphism was independent of age and conventional risk factors. Conclusions: Genotyping of these polymorphisms may prove informative for assessment of the genetic risk of CAD in low- or high-risk men or women. Perspective: Identifying single nucleotide polymorphisms (SNPs) of genes involved in atherosclerosis through lipid metabolism, thrombosis, inflammation and vascular matrix metabolism has been used to characterize genetic vs. environmental risk in several ethnic groups. As in hypertension, the contribution of SNPs is likely the tip of a huge iceberg. I suspect we may be floating on the Titanic for many years, particularly in the US with the ever increasing ethnic/racial diversity from immigration and intermarriage. MR
Comparing Symptoms of Depression and Anxiety as Predictors of Cardiac Events and Increased Health Care Consumption After Myocardial Infarction
A Polymorphism of the Cholesterol Ester Transfer Protein Gene Predicts Cardiovascular Events in Non-smokers in the West of Scotland Coronary Prevention Study
Strik JJM, Denollet J, Lousberg R, Honig A. J Am Coll Cardiol 2003;42:1801–7.
Freeman DJ, Samani NJ, Wilson V, et al., on behalf of the West of Scotland Study Group. Eur Heart J 2003;24:1833– 42.
Study Question: Do anxiety and depression effect post-MI mortality and health care resource consumption?
ACC CURRENT JOURNAL REVIEW Mar 2004
26