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CLINICAL STUDIES

Angiotensin I–converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort

Bastiaan T. Heijmans, MSc^* , Rudi G. J. Westendorp, MD, PhD , Dick L. Knook, PhD^* , Cornelis Kluft, PhD^* and P. Eline Slagboom, PhD^*

^* Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
Section of Gerontology and Geriatrics, Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

Manuscript received December 31, 1998; revised manuscript received May 7, 1999, accepted June 23, 1999.

Reprint requests and correspondence: Dr. P. E. Slagboom, TNO Prevention and Health, Gaubius Laboratory, Zernikedreef 9, P.O. Box 2215, 2301 CE, Leiden, The Netherlands

OBJECTIVES

We studied the contribution of putative risk genotypes at the angiotensin I–converting enzyme inhibitor (ACE D/D) and plasminogen activator inhibitor-1 (PAI-1 4G/4G) loci to all-cause and cardiovascular mortality in a population-based cohort.

BACKGROUND

The ACE D/D and PAI-1 4G/4G genotypes have been consistently associated with elevated plasma activities of the gene products. Their role in cardiovascular disease, although explored intensively, is still equivocal.

METHODS

The ACE and PAI-1 genotypes were determined in 648 subjects 85 years old. In a cross-sectional analysis, the genotype distributions in a subset of 356 elderly subjects who were born in Leiden, The Netherlands, were compared with those in 250 young subjects whose families originated from the same geographic region. In addition, the complete cohort of elderly subjects was followed over 10 years for all-cause and cardiovascular mortality and was stratified according to genotype.

RESULTS

In the cross-sectional analysis, the ACE and PAI-1 genotype distributions were similar in elderly and young subjects. In the prospective follow-up study, however, the age-adjusted risk of fatal ischemic heart disease was increased threefold (95% confidence interval [CI] 1.2 to 7.6) in elderly men carrying the PAI-1 4G/4G genotype. The risk of all-cause mortality was not increased among elderly subjects carrying the PAI-1 4G/4G (relative risk [RR] 0.9, 95% CI 0.7 to 1.1) or the ACE D/D genotype (RR 0.9, 95% CI 0.7 to 1.1), nor did we observe elevated risks of death from all cardiovascular diseases combined. There was no interaction between the genotypes.

CONCLUSIONS

The PAI 4G/4G genotype may be a risk factor for fatal ischemic heart disease in elderly men. The impact of moderately increased ACE and PAI-1 activities associated with the ACE D/D and PAI-1 4G/4G genotypes is too small to affect mortality in the general population.

Abbreviations and Acronyms   ACE = angiotensin I–converting enzyme   CI = confidence interval   I/D = insertion/deletion   PAI-1 = plasminogen activator inhibitor-1   PCR = polymerase chain reaction   RR = relative risk

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