Pharmacogenetic Association of the Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism on Blood Pressure and Cardiovascular Risk in Relation to Antihypertensive Treatment

Abstract

Background-Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes. Methods and Results-We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives Ն55 years of age with Ն1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up.

Angiotensin-converting enzyme single nucleotide polymorphism is a genetic risk factor for cardiovascular disease: a cohort study of hypertensive patients

“…Subjects with the DD genotype exhibited higher tissue ACE activity and increased ACE expression in the plaque of acute coronary syndrome, observations that may explain why hypertensive patients with the DD genotype have a higher incidence of cardiovascular disease. In contrast, in the GenHAT study, 15 the ACE I/D genotype was not a predictor of CVD, nor did it modify the response to antihypertensive treatment. A major difference between the present cohort study and the GenHAT study is the race of the participants.…”

“…18 Although some studies have reported that administration of ACE-Is and/or ARBs vary the effect of the ACE I/D genotype on cardiovascular events, 25 others have not. 15 Although we only have baseline information about antihypertensive treatments, the ACE DD genotype was an independent risk factor for CVD after adjusting for ACE-I/ARB drugs and antihypertensive drugs. A previous report 26 revealed an association between aldosterone escape and the DD genotype, suggesting an influence by aldosterone escape.…”

“…Our assumption that ACE-Is and/or ARBs impacted the influence of these SNPs has been demonstrated previously; 18 therefore, we also adjusted for CVD risk factors, ACE-I administration, and/or ARB administration in Model 4. To evaluate the influence of high-risk patients included in GenHAT, 15 we selected advanced CVD risk factors such as left ventricular hypertrophy shown on ECG or echocardiography, and previous MI and stroke (Table 3b).…”

“…The GenHAT study, a sub-analysis of the ALLHAT study, reported that the ACE I/D polymorphism conferred no genetic risk for cardiovascular diseases; 15 however, the genetic frequencies of the ACE I/D polymorphism are quite different, and a cohort study of hypertensive patients in Japan was not reported. Here, we investigate whether three RAS genotypes interact with the risk of CVD in hypertensive patients in Japan.…”

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor

“…27 Our findings could contribute to the understanding of the pharmacogenetics of ACErelated drugs. Although no pharmacogenetic association between ACE insertion/deletion genotype and blood pressure response was identified in a large-scale clinical trial study, 28 it is shown by us in people with a relatively high number of ACE-activity-raising alleles/genotypes, those who take the ACEI show a lower mean blood pressure values than those who do not. Conversely, in people having no such alleles, disadvantageously higher mean blood pressure values are observed in those taking ACEI than those not.…”