Bastiaan T. Heijmans, MS ,*† Rudi G. J. Westendorp, MD, P D,†‡ Dick L. Knook, P D,*† C H H Cornelis Kluft, P D,* P. Eline Slagboom, P D* H H Leiden, The Netherlands

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.

We studied the contribution of putative risk genotypes at the angiotensin I–converting enzyme inhibitor (ACE D/D) and plasminogen activator inhibitor-

(PAI-

G/

G) loci to all-cause and cardiovascular mortality in a population-based cohort. BACKGROUND The ACE D/D and PAI-

G/

G 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-

genotypes were determined in

subjects $

years old. In a cross-sectional analysis, the genotype distributions in a subset of

elderly subjects who were born in Leiden, The Netherlands, were compared with those in

young subjects whose families originated from the same geographic region. In addition, the complete cohort of elderly subjects was followed over

years for all-cause and cardiovascular mortality and was stratified according to genotype. RESULTS In the cross-sectional analysis, the ACE and PAI-

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 (

% confidence interval [CI]

to

) in elderly men carrying the PAI-

G/

G genotype. The risk of all-cause mortality was not increased among elderly subjects carrying the PAI-

G/

G (relative risk [RR]

,

% CI

to

) or the ACE D/D genotype (RR

,

% CI

to

), nor did we observe elevated risks of death from all cardiovascular diseases combined. There was no interaction between the genotypes. CONCLUSIONS The PAI

G/

G genotype may be a risk factor for fatal ischemic heart disease in elderly men. The impact of moderately increased ACE and PAI-

activities associated with the ACE D/D and PAI-

G/

G genotypes is too small to affect mortality in the general population. (J Am Coll Cardiol

;

:

–

) ©

by the American College of Cardiology

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

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

RESULTS In the cross-sectional analysis, the ACE and PAI-

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 (

% confidence interval [CI]

to

) in elderly men carrying the PAI-

G/

G genotype. The risk of all-cause mortality was not increased among elderly subjects carrying the PAI-

G/

G (relative risk [RR]

,

% CI

to

) or the ACE D/D genotype (RR

,

% CI

to

), nor did we observe elevated risks of death from all cardiovascular diseases combined. There was no interaction between the genotypes. CONCLUSIONS The PAI

G/

G genotype may be a risk factor for fatal ischemic heart disease in elderly men. The impact of moderately increased ACE and PAI-

activities associated with the ACE D/D

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. (J Am Coll Cardiol 1999;34:1176–83) © 1999 by the American College of Cardiology

Over the last years a number of common gene variants have been identified that are associated with plasma levels of the gene products and the risk of cardiovascular disease. Most studies performed thus far have not addressed the associa- tion of these variants with fatal cardiovascular disease or have only included a small number of fatal cases. Also, very

few studies have yet explored how combinations of possible risk genotypes affect disease risk. Establishing such genetic risk profiles is only feasible when relatively large populations are available and the putative risk alleles have a high frequency in the general population. Two highly frequent genetic variants that may be linked to cardiovascular disease risk have been identified in the genes encoding angiotensin I–converting enzyme (ACE) inhibitor and plasminogen

From the *Gaubius Laboratory, TNO Prevention and Health, Leiden; †Section of Gerontology and Geriatrics, Department of General Internal Medicine, Leiden University Medical Center, Leiden; and ‡Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. This study was supported by grant 94.047 from the Netherlands Heart Foundation and grant AG06354 from the National Institutes of Health, Bethesda, Maryland.