Angiotensin converting enzyme gene polymorphism and myocardial infarction a large association and linkage study

Abstract

The DD genotype of the angiotensin converting enzyme (ACE) polymorphism has been associated with myocardial infarction (MI). However, sample sizes of many case-control studies showing positive association were small and data were inconsistent. Furthermore, no family-based study is available.

In a case-control study frequencies of the ACE genotypes were compared in 1319 unrelated patients with previous MI before 60 years of age (616 from the MONICA Augsburg region and 703 from rehabilitation centers in south Germany) and in 2381 population controls from the MONICA Augsburg study region). Furthermore, linkage and association of the ACE I/D polymorphism with MI were tested in 246 informative families using the sib-transmission/disequilibrium test (S-TDT).

Overall, no excess of the D allele was found in MI patients (frequency 0.53 versus 0.57 in the general population; P=0.2). The ACE DD genotype was even slightly less frequent in groups with MI compared to the general population controls (0.26 versus 0.33 in women and 0.28 versus 0.33 in men). Similar results were also obtained in 247 men with low cardiovascular risk. In the family-based study, the frequency of the D allele was not different in siblings with or without previous MI (0.53 versus 0.50, respectively; S-TDT P=0.15) indicating no linkage or association of the D allele with MI.

In a case-control study of MI patients and controls from the general population as well as a family study neither association nor linkage of the ACE D allele with MI was detected despite sample sizes that were among the largest samples studied so far.

Introduction

Since the first report in 1992 [1] controversy exists whether the D allele of the insertion/deletion polymorphism (I/D) of the human angiotensin I-converting enzyme (dipeptidyl carboxypeptidase 1; DCP1, ACE) gene influences the risk of myocardial infarction (MI). Although the molecular mechanism that explains higher ACE activity in carriers of the D allele has not been elucidated a large body of data conclusively demonstrates higher plasma and tissue ACE activity in these individuals [2], [3], [4], [5]. As a consequence, angiotensin II levels may be higher, as well. Interestingly, the I/D polymorphism was found to be in linkage disequilibrium with 19 other polymorphisms within the ACE gene [6]. It is unclear, however, whether the heterogeneity of polymorphisms within the ACE gene that was observed in individuals from different ethnic background (European–American versus African–American) may explain conflicting results of published studies [3], [7].

A meta-analysis of 19 study populations that examined the association with MI (in a total of 3394 MI cases and 5479 controls) calculated a mean odds ratio for the DD genotype versus ID and II genotypes of 1.26 (range of studies between 0.95 and 3.83) [7]. It was calculated that in order to provide sufficient power for detection of this relative risk a single association study would require approximately 1400 cases and the same number of controls. Of all association studies published so far only negative studies met this requirement [8], [9]. Considering that positive studies may be favored with respect to acceptance for publication despite small sample size the relative risk attributable to the DD genotype may even be less than estimated by meta-analyses based on published association studies [8].

So far, no evidence has been presented for linkage of the ACE locus with myocardial infraction in family-based studies. Traditional linkage analyses have been hampered by the fact that suitable families with multiple affecteds are rarely available.

Therefore, we evaluated the role of the ACE gene I/D polymorphism as independent risk factor for MI in an association study that includes 1322 MI cases and 2381 controls from a general population in middle Europe. Furthermore, we tested for linkage and association of the I/D polymorphism with myocardial infarction in a family-based approach using a sib transmission/disequilibrium test (S-TDT) in 246 families with at least one member with previous MI.