not reported in the text, it is unclear whether the twins were monozygotic or dizygotic. Therefore, I will not make any assumptions about their zygosity.

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 684 twins aged 73 years from the 1997 and 1999 surveys of the Longitudinal 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 performance 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), respectively.

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

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

INTRODUCTION

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 on chromosome 17. The fragment is present in the insertion (I) variant and absent in the deletion (D) variant, which results in three genotypes: Homozygotes II and DD and heterozygotes DI. The genotype accounts for approximately 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 genotype) (1). The cleavage of angiotensin-I by ACE produces the octapeptide angiotensin-II, which is a potent vasoconstrictor. The relationship between ACE genotypes, particularly 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 explanation for this discrepancy (2).

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 genotype was associated with improved performance (36). 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 (36).

Physical performance is important for younger people but even more so among the elderly where physical performance together with cognitive function determine whether life can be lived independently. Cognitive impairment and dementia have also been reported to be associated with ACE genotype, although recent studies have come to opposite conclusions regarding ACE genotype and risk for Alzheimer's disease (AD) (7, 8). An increased risk of AD was associated with the I allele in one study (7), but the D allele in another (8).

It has been suggested that mortality risk may be influenced by ACE genotype since a German study found an increased frequency of the DD genotype in octogenarians (9). This finding could not, however, be confirmed in two large studies of centenarians (10, 11). Studies of elderly twins have found evidence of substantial genetic influence on both physical (14) and cognitive functioning (15, 16) as well as a moderate genetic influence on lifespan (17). Twin studies have mostly been used for determining the relative contribution of genes and environment to the variation of a phenotype but less so for identifying specific genetic variants of importance. Based on the previous association studies and the fact that the renin-angiotensin system is involved in cardiovascular and renal homeostasis and that ACE activity and angiotensin receptors can be demonstrated inCorrected Text:

Determined through a self-report questionnaire, a method that has been shown to result in less than 5 percent misclassification (19), the number of misclassified MZ twins was very small.

Genotyping:
The ACE genotyping was done according to Rigat et al. (20). To avoid the earlier reported mistyping of ACE heterozygotes (ID genotypes misclassified as DD) (21, 22), all samples typed as DD were re-amplified as described by Shanmugam et al. (21) with another set of primers in the presence of a positive control (ID/II).