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      Genetics and Gene Manipulation Therapy of Premature Coronary Artery Disease

      , ,
      S. Karger AG
      Coronary artery disease, premature, Genetics, Gene therapy

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          Despite the notable recent scientific advances, our ability to detect and prevent premature coronary artery disease (CAD) remains limited, and the identification of patients at risk is yet to be based on objective scientific testing. Eliciting a family history of CAD currently remains the only available screening tool to identify patients with a genetic predisposition. The risk of CAD attributable to genes appears to be most significant at younger ages, and this may explain the lack of definite markers for the disease. Candidate gene association studies focusing on young patients with CAD will, therefore, be more likely to identify a true genetic risk. In this report, we review the known genetic risk factors for premature CAD. We also discuss the potential gene manipulation therapy of CAD as well as of vein graft atherosclerosis following coronary artery bypass surgery.

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          Genetic susceptibility to death from coronary heart disease in a study of twins.

          A family history of premature coronary heart disease has long been thought to be a risk factor for coronary heart disease. Using data from 26 years of follow-up of 21,004 Swedish twins born between 1886 and 1925, we investigated this issue further by assessing the risk of death from coronary heart disease in pairs of monozygotic and dizygotic twins. The study population consisted of 3298 monozygotic and 5964 dizygotic male twins and 4012 monozygotic and 7730 dizygotic female twins. The age at which one twin died of coronary heart disease was used as the primary independent variable to predict the risk of death from coronary heart disease in the other twin. Information about other risk factors was obtained from questionnaires administered in 1961 and 1963. Actuarial life-table analysis was used to estimate the cumulative probability of death from coronary heart disease. Relative-hazard estimates were obtained from a multivariate survival analysis. Among the men, the relative hazard of death from coronary heart disease when one's twin died of coronary heart disease before the age of 55 years, as compared with the hazard when one's twin did not die before 55, was 8.1 (95 percent confidence interval, 2.7 to 24.5) for monozygotic twins and 3.8 (1.4 to 10.5) for dizygotic twins. Among the women, when one's twin died of coronary heart disease before the age of 65 years, the relative hazard was 15.0 (95 percent confidence interval, 7.1 to 31.9) for monozygotic twins and 2.6 (1.0 to 7.1) for dizygotic twins. Among both the men and the women, whether monozygotic or dizygotic twins, the magnitude of the relative hazard decreased as the age at which one's twin died of coronary heart disease increased. The ratio of the relative-hazard estimate for the monozygotic twins to the estimate for the dizygotic twins approached 1 with increasing age. These relative hazards were little influenced by other risk factors for coronary heart disease. Our findings suggest that at younger ages, death from coronary heart disease is influenced by genetic factors in both women and men. The results also imply that the genetic effect decreases at older ages.
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            Adenoviruses as gene-delivery vehicles.

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              The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men.

              Inflammation is a key component of coronary heart disease, and genes coding for cytokines are candidates for predisposing to coronary heart disease risk. We have examined the effect of two polymorphisms (-174G>C and -572G>C) in the promoter of the interleukin-6 (IL-6) gene on risk of coronary heart disease, and on intermediate risk traits including fibrinogen and systolic blood pressure, in 2751 middle-aged healthy U.K. men. The -174C allele (frequency 0.43, 95% CI 0.42-0.44) was not associated with significant effects on fibrinogen levels, but was associated with a significantly (P=0.007) higher systolic blood pressure (mean mmHg (95% CI): GG=135.5 (134.3-136.7); GC=137.9 (136.9-138.9); CC= 138.0 (136.3-139.8)). This effect was of similar magnitude in smokers and non-smokers, and was greater in men in the top two tertiles of body mass index (>24.86 kg x m(-2)) than in those in the bottom tertile. Compared to those with the genotype GG, men carrying the -174C allele had a relative risk of coronary heart disease of 1.54 (95% CI 1.0-2.23, P=0.048) and this effect was greatest in smokers (compared to GG non-smokers, RR 2.66, CI 1.64-4.32). These effects remained statistically significant after adjusting for classical risk factors including blood pressure (P=0.04). The -572C allele (frequency 0.05, 0.04-0.06) was not associated with a significant effect on blood pressure, fibrinogen or relative risk of coronary heart disease. In a subset of the genotyped men (n=494), carriers of the -174C allele had higher levels of C-reactive protein than non-carriers. These data confirm the importance of the inflammatory system in the development of coronary heart disease. They suggest that, at least in part, the effect of the IL-6 -174G>C polymorphism on blood pressure is likely to be operating through inflammatory mechanisms, but the genotype effect on coronary heart disease risk is largely unexplained by its effect on blood pressure. The molecular mechanisms whereby genetically determined differences in plasma levels of IL-6 are having these effects remain to be determined. Copyright 2001 The European Society of Cardiology.

                Author and article information

                S. Karger AG
                February 2004
                27 February 2004
                : 101
                : 1-3
                : 122-130
                Division of Cardiothoracic Surgery, Department of Surgery, The University of Illinois College of Medicine at Chicago, Chicago, Ill., USA
                75993 Cardiology 2004;101:122–130
                © 2004 S. Karger AG, Basel

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                Page count
                Tables: 2, References: 68, Pages: 9

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Genetics,Coronary artery disease, premature,Gene therapy


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