The Health Outcome

Americans are more likely to die of heart disease or stroke than any other cause. In 2002, cardiovascular disease (CVD) claimed 38% of all deaths, surpassing the burden of cancer, injuries and HIV (2). The U.S mortality rate from CVD that year was 375 per 100,000 (adjusted to the standard U.S. population in 2000). (2)

According to the American Heart Association, the average annual rate of first major cardiovascular event rises from 7 per 1,000 men at ages 35–44 to 68 per 1,000 at ages 85–94. Among women, comparable rates occur 10 years later in life. As such, the aging of the population will increase the incidence of CVD (2).

Heart disease is the leading cause of premature, permanent disability in the U.S. workforce. Two-thirds of those who experience myocardial infarction (MI) fail to recover fully. Stroke can dramatically diminish the ability of survivors to function autonomously and 20% of stroke survivors require institutional care (3).

CVD patients have to deal with the cost of treatment, the side effects of medications and the possibility of disability and dependency. The financial burden of CVD is immense, estimated in the U.S in 2004 as $368.4 billion in direct and indirect costs (3).

An insertion (I)/deletion (D) polymorphism situated in intron 16 of the angiotensin converting enzyme (ACE) gene—known as the ACE I/D polymorphism—was implicated in coronary artery disease more than 10 years ago (4). The polymorphism is strongly associated with the level of circulating ACE. The mean plasma ACE level in subjects who have the DD genotype is about twice that in subjects with the II genotype, with ID subjects having intermediate levels (5). Administration of an ACE inhibitor has been shown to decrease the risk of heart failure and recurrent myocardial infarction (MI) (6). Results of previous studies of the association of ACE I/D with MI and coronary heart disease (CHD) have been inconsistent. CHD is a multi-factorial disease, likely to result from
interactions among many genes and environmental exposures. The previous study of the authors showed a significant association between smoking and ACE plasma level. There is also published evidence of an
interaction between the ACE I/D polymorphism and smoking in relation to carotid intima media thickness. The biological plausibility of such an interaction prompted the authors to study smoking as an effect modifier of the association between the ACE gene polymorphism and CVD mortality and morbidity (1).

The Finding

This study was nested in the Rotterdam Study, a population-based, prospective cohort study. Smoking status was recorded at baseline and the ACE I/D polymorphisms were determined for 6714 participants. Genotyping was performed by PCR using two different primers. Clinics and primary care providers regularly recorded morbidity and mortality. Cox proportional hazard analysis was performed separately for current smokers and non-smokers; age was used as the follow-up time in presenting results of survival analysis.

Among young smokers (<68.2 years, the median age of the cohort), there was an increased risk of CVD mortality in carriers of the DD genotype compared with the II genotype. The hazard ratio for ACE DD/II was 5.19 (95% CI 1.15--23.42; p<0.01 for gene-age in tera ction). There was some suggestion of a trend with respect to the effect of the D allele; the hazard ratio for ACE DI/II was 1.19 (95% CI 0.41—9.00).

Risk of CHD mortality was increased among young smokers with the DD genotype compared with the II genotype; the hazard ratio was 7.33 (95% CI 0.92—58.65; p<0.02 for gene-age in tera ction). There was some suggestion of a trend with respect to the effect of the D allele; the hazard ratio for ACE DI/II was 2.78 (95% CI 0.33—23.10). No significant association between MI and the ACE gene was found.

Public Health Implications

With caution, we can infer that the ACE genotype interacts with smoking and age to increase the risk of CVD mortality, with the DD genotype being the susceptible variant among young smokers.

Census 2000 data show that the approximate percentage of Americans who are 68 years old or below is 87.5% (13). The estimated 28% who have the DD genotype might be at an increased risk of CVD if they smoke. However, smoking is a major risk factor for CVD and other chronic diseases such as lung cancer, regardless of genotype. Therefore, the results of this study do not have immediate public health implications.

The decrease in cardiovascular disease mortality in the United States between 1971-1982 and 1982-1992 has been attributed to declines in both the incidence and case fatality rates. This suggests that both primary and secondary prevention and treatment contributed to the decline (15). Although this study does not introduce a new avenue for public health intervention, it still sheds some light on the biology of CVD.

References

1. Sayed-Tabatabaei FA, et al. Angiotensin Converting Enzyme gene polymorphism and cardiovascular morbidity and mortality: the Rotterdam Study. Journal of Medical Genetics. 2005;42:26-30.
2. Crowell A, et al. Chronic Disease Notes & Reports: Heart Disease Burden. Centers for Disease Control and Prevention. 2004; fall, Vol. 17 Number 1.
3. Heart Disease and Stroke Statistics — 2005 Update. American Heart Association.
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5. Rigat, et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343–6.
6. Lindpaintner K, et al. A prospective evaluation of an angiotensinconverting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706–11.
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11. McNamara DM, et al. Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol. 2004; Nov 16,44 (10):2019-26.
12. MB Juckett, et al. Post-transplant complications Loss of renal function following bone marrow transplantation: an analysis of angiotensin converting enzyme D/I polymorphism and other clinical risk factors. J Investig Med. 2003; Nov,51(6):360-5.
13. CensusScope—Population pyramid and age distribution statistics. URL http://www.censusscope.org/us/chart_age.html
14. Kannel, et al. Blood Pressure Cardiovascular Risk Gradient. Hypertension. 2003; October
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16. Touboul PJ, et al. Mannheim Intima-Media Thickness Consensus. Cerebrovasc Dis 2004;18:346–349
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