Linkage and Association Analysis of Angiotensin I–Converting Enzyme (ACE)–Gene Polymorphisms with ACE Concentration and Blood Pressure

Abstract

Considerable effort has been expended to determine whether the gene for angiotensin I-converting enzyme (ACE) confers susceptibility to cardiovascular disease. In this study, we genotyped 13 polymorphisms in the ACE gene in 1,343 Nigerians from 332 families. To localize the genetic effect, we first performed linkage and association analysis of all the markers with ACE concentration. In multipoint variance-component analysis, this region was strongly linked to ACE concentration (maximum LOD score 7.5). Likewise, most of the polymorphisms in the ACE gene were significantly associated with ACE (P<.0013). The two most highly associated polymorphisms, ACE4 and ACE8, accounted for 6% and 19% of the variance in ACE, respectively. A two-locus additive model with an additive x additive interaction of these polymorphisms explained most of the ACE variation associated with this region. We next analyzed the relationship between these two polymorphisms (ACE4 and ACE8) and blood pressure (BP). Although no evidence of linkage was detected, significant association was found for both systolic and diastolic BP when a two-locus additive model developed for ACE concentration was used. Further analyses demonstrated that an epistasis model provided the best fit to the BP variation. In conclusion, we found that the two polymorphisms explaining the greatest variation in ACE concentration are significantly associated with BP, through interaction, in this African population sample. Our study also demonstrates that greater statistical power can be anticipated with association analysis versus linkage, when markers in strong linkage disequilibrium with a trait locus have been identified. Furthermore, allelic interaction may play an important role in the dissection of complex traits such as BP.

Association of the angiotensin-converting enzyme (ACE) gene G2350A dimorphism with essential hypertension

“…32 It was then described as ACE-8 by Zhu et al, 33 as a modification by introducing a mismatch guanine at the 3 0 end of the primer sequence, resulting in the amplification of a BstU1 restriction site. This more convenient method involves a set of primers designed to amplify a 122-bp fragment encompassing the polymorphic region of ACE gene: 5 0 -CTGACGAATGTGATGGCCGC 3 0 (upstream) and 5 0 -TTGATGAGTTCCACGTATTTCG-3 0 (downstream).…”

“…16 Among the 13 polymorphisms of the ACE gene recently reported, a dimorphism in exon 17, ACE G2350A, has the most significant effect on plasma ACE concentrations. 33 After adjustment for the effect of ACE G2350A dimorphism, the I/D dimorphism was no longer associated with ACE, indicating that it is in LD with ACE G2350A and unlikely to be a functional mutation. 33 To assess the value of genotyping of ACE in a genetically homogeneous population, we carried out a retrospective case-control study of dimorphism G2350A for a putative association with EH among nationals from the United Arab Emirates (Emirati)-Fan ethnic group characterized by no alcohol intake and no cigarette smoking.…”

“…33 After adjustment for the effect of ACE G2350A dimorphism, the I/D dimorphism was no longer associated with ACE, indicating that it is in LD with ACE G2350A and unlikely to be a functional mutation. 33 To assess the value of genotyping of ACE in a genetically homogeneous population, we carried out a retrospective case-control study of dimorphism G2350A for a putative association with EH among nationals from the United Arab Emirates (Emirati)-Fan ethnic group characterized by no alcohol intake and no cigarette smoking. Our studies aimed at establishing whether the ACE G2350A dimorphism is a genetic marker and an independent risk factor for EH.…”

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans

“…8 Numerous studies have explored the association between polymorphisms in the ACE gene and EH, but the results are conflicting. 9,10 In particular, the results of association studies differ between populations. [11][12][13] One of the most extensively studied RAAS factors is the insertion/deletion (I/D) polymorphism of the ACE gene.…”

The effect of genetic variation in angiotensinogen on serum levels and blood pressure: a comparison of Nigerians and US blacks

“…One way to decrease the genetic heterogeneity and increase the power in genetic studies of human complex diseases is to follow a two-stage approach: first studying an intermediate phenotype and then testing the significant results in a study of the clinically relevant end point. 2 Over the last decade, a series of reports have investigated the association between angiotensinogen (AGT) variants with AGT level and HT. [3][4][5][6][7][8] However, the overall results are inconsistent.…”