PAI-1 4G/5G polymorphism. We found that men 85 years old carrying the PAI-1 4G/4G genotype were at a threefold increased risk of death due to ischemic heart disease during a 10-year follow-up period. This was not reflected in the risk of death from all cardiovascular causes combined or increased mortality before the age of 85 years. The indication that the PAI-1 polymorphism may contrib- ute to the development of ischemic heart disease in old age significantly extends the previous findings that the PAI-1 4G/4G genotype is a risk factor for premature myocardial , infarction, which has a much lower incidence (patients 45 years old [18], mean age 58 years [24,26]). It should, however, be noted that although our study is prospective and thus not prone to bias, our findings are based on the analysis of a small subset and therefore require confirmation in more extensive studies.

Study limitations. Our study indicates that it is unlikely that the putative ACE and PAI-1 risk genotypes have a major influence on mortality in the population at large. On the basis of the 95% CIs, the overall mortality risks can be , expected to be 1.2-fold increased. The current study does not, however, have sufficient power to exclude associations between polymorphisms and specific causes of death, owing to the relatively small numbers of subjects in these subsets. In these subsets, nondifferential misclassification of causes of death could be expected to have occurred because they were not confirmed at necropsy, which leads to an under- estimation of the risk estimates. We have previously re- ported associations with single specific causes of death, indicating that the registry data have significant power to

In contrast to our studies and those mentioned earlier, as well as a study showing a higher prevalence of the PAI-1 4G/4G genotype among subjects with a family history of

ACE and PAI-1 Gene Variants and Mortality

in the angiotensin converting enzyme gene is not associated with coronary heart disease in an Austrian population. Atherosclerosis

;

:

–

Agerholm-Larsen B, Nordestgaard BG, Steffensen R, et al. ACE gene polymorphism: ischemic heart disease and longevity in

,

indi- viduals—a case-referent and retrospective cohort study based on the Copenhagen City Heart Study. Circulation

;

:

–

Samani NJ, O’Toole L, Martin D, et al. Insertion/deletion polymor- phism in the angiotensin-converting enzyme gene and risk of and prognosis after myocardial infarction. J Am Coll Cardiol

;

:

–

Bohn M, Berge KE, Bakken A, et al. Insertion/deletion (I/D) polymorphism at the locus for angiotensin I–converting enzyme and myocardial infarction. Clin Genet

;

:

–

Gardemann A, Fink M, Stricker J, et al. ACE I/D gene polymor- phism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals. Atherosclerosis

;

:

–

Mattu RK, Needham EW, Galton DJ, et al. A DNA variant at the angiotensin-converting enzyme gene locus associates with coronary artery disease in the Caerphilly Heart Study. Circulation

;

:

–

Scha¨chter F, Faure Delanef L, Gue´not F, et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet

;

:

–

Dawson SJ, Wiman B, Hamsten A, et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-

(PAI-

) gene respond differently to interleukin-

in He

cells. J Biol Chem

;

:

–

Eriksson P, Kallin B, van ’t Hooft FM, et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor

gene is associated with myocardial infarction. Proc Natl Acad Sci USA

;

:

–

Ye S, Green FR, Scarabin PY, et al. The

G/

G genetic polymor- phism in the promoter of the plasminogen activator inhibitor-

(PAI-

) gene is associated with differences in plasma PAI-

activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost

;

:

–

Panahloo A, Mohamed Ali V, Lane A, et al. Determinants of plasminogen activator inhibitor

activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor

gene. Diabetes

;

:

–

Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activa- tor inhibitor-

in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost

;

:

–

Eriksson P, Nilsson L, Karpe F, Hamsten A. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-

gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol

;

:

–

Ridker PM, Hennekens CH, Lindpaintner K, et al. Arterial and venous thrombosis is not associated with the

G/

G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of U.S. men. Circulation

;

:

–

Ossei Gerning N, Mansfield MW, Stickland MH, et al. Plasminogen activator inhibitor-

promoter

G/

G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arterioscler Thromb Vasc Biol

;

:

–

Margaglione M, Cappucci G, Colaizzo D, et al. The PAI-

gene locus

G/

G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol

;

:

–

Pastinen T, Perola M, Niini P, et al. Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population. Hum Mol Genet

;

:

–

Ridker PM, Gaboury CL, Conlin PR, et al. Stimulation of plasmin- ogen activator inhibitor in vivo by infusion of angiotensin II: evidence of a potential interaction between the renin–angiotensin system and fibrinolytic function. Circulation

;

:

–

Kim DK, Kim JW, Kim S, et al. Polymorphism of angiotensin