Angiotensin I-Converting Enzyme (ACE) Gene Polymorphism in Relation to Physical Performance, Cognition and Survival—A Follow-up Study of Elderly Danish Twins

HENRIK FREDERIKSEN, MD, DAVID GAIST, MD, PHD, LISE BATHUM, MD, PHD, KJELD ANDERSEN, MD, PHD, MATT MCGUE, PHD, JAMES W. VAUPEL, PHD, AND KAARE CHRISTENSEN, MD, PHD

PURPOSE: Studies of younger individuals have suggested an association between ACE genotype and physical and cognitive performance. Using a longitudinal study of elderly twins we studied the association between ACE genotype and physical and cognitive functioning and survival in old age.

METHODS: Participants were

twins aged

(cid:

) years from the

and

surveys of the Longitu- dinal Study of Aging Danish Twins. Cognitive skills were assessed by the MMSE, while physical abilities were determined through self-report in

and through both self-report and measurement of perfor- mance in two physical tasks in

Survival status was obtained through linkage with a national death register. RESULTS: Neither physical nor cognitive performance was associated with ACE genotype at baseline in

, or at follow-up in

For participants in both surveys longitudinal changes in these skills did not depend on ACE genotype. The relative risk of dying was increased in II compared with the DI and DD genotype with relative risks of

(

percent confidence intervals

–

) and

(

–

), respec- tively. CONCLUSION: We found no substantial effects of ACE genotype on physical and cognitive perfor- mance, or rate of change among elderly. Persons with the D allele may have a lower mortality at older ages. Ann Epidemiol

;

:

–

©

Elsevier Science Inc. All rights reserved.

METHODS: Participants were 684 twins aged 73(cid:2) years from the 1997 and 1999 surveys of the Longitu- dinal Study of Aging Danish Twins. Cognitive skills were assessed by the MMSE, while physical abilities were determined through self-report in 1997 and through both self-report and measurement of perfor- mance in two physical tasks in 1999. Survival status was obtained through linkage with a national death register.

RESULTS: Neither physical nor cognitive performance was associated with ACE genotype at baseline in 1997, or at follow-up in 1999. For participants in both surveys longitudinal changes in these skills did not depend on ACE genotype. The relative risk of dying was increased in II compared with the DI and DD genotype with relative risks of 1.6 (95 percent confidence intervals 1.1–2.5) and 1.3 (0.8–2.1), respec- tively.

We found no substantial effects of ACE genotype on physical and cognitive or rate of change among elderly. Persons with the D allele may have a lower mortality at

WORDS: Genetics, Epidemiology, Aging, Polymorphism (Genetics), Physical Fitness, Twins.

INTRODUCTION

DD and heterozygotes DI. The genotype accounts for ap- proximately half of the variance in the circulating ACE level and from the II to the DD genotype the presence of each D allele is associated with an additive effect on ACE activity (50% higher in the DD compared with the II geno- type) (1). The cleavage of angiotensin-I by ACE produces the octapeptide angiotensin-II, which is a potent vasocon- strictor. The relationship between ACE genotypes, in par- ticular DD, and the occurrence of cardiovascular and renal diseases has therefore been the focus of several studies in the past decade. The results from these association studies have not been consistent, and for ischemic heart disease publication bias has recently been shown to be a likely ex- planation for this discrepancy (2).

A polymorphism in the gene coding for Angiotensin I-Converting Enzyme (ACE) was identified in 1990 (1). The polymorphism is due to a 287 bp fragment in the ACE gene in chromosome 17. The fragment is present in the in- sertion (I) variant and absent in the deletion (D) variant, which results in the three genotypes: Homozygotes II and

From the Department of Epidemiology, Institute of Public Health, Uni- versity of Southern Denmark, Main Campus: Odense University (H.F., D.G., K.A., K.C.); Department of Clinical Biochemistry, Odense Univer- sity Hospital (L.B.); Department of Psychology, University of Minnesota, Minneapolis, (M.M.); Max Planck Institute for Demographic Research, Rostock, Germany (J.W.V.); and the Danish Center for Demographic Re- search, University of Southern Denmark, Main Campus: Odense Univer- sity (K.C.).

In the past few years the ACE gene polymorphism has also been associated with the outcome of physical exercise, especially endurance performance. Presence of the II geno- type was associated with improved performance (3–6). However, the study subjects were mostly young healthy males from highly selected populations (e.g. elite athletes and military recruits) and the samples were small (3–6).

Address correspondences to: Kaare Christensen, MD, PhD, Research Professor, Institute of Public Health, Epidemiology University of Southern Denmark, Sdr. Boulevard 23a, DK-5000, Odense C., Denmark. Tel.: (cid:2)45 65 50 30 49, Fax: (cid:2)45 65 90 69 38, E-mail: kchristensen@health. sdu.dk Received July 5, 2001; revised December 13, 2001; accepted December

Received July 5, 2001; revised December 13, 2001; accepted December 27, 2001.

relationship of ACE genotype to cognitive performance and survival. Due to the well-established association between the I/D genotype and the stepwise phenotypic expression of the ACE gene (1) it could further be hypothesized that any association with examined phenotypes would result in step- wise trends in the differences.

MATERIAL AND METHODS

Study Population