Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men

Abstract

Angiotensin-converting enzyme (ACE) activity is considered to be of major importance for the conversion of angiotensin (Ang) I to Ang II. Recently, a second ACE, named ACE2, has been identified. Experimental data provide evidence that ACE2 might be involved in modulating cardiac structure and function. In the present explorative study, we assessed whether polymorphisms in the ACE2 gene are related to echocardiographically determined parameters of left ventricular mass, structure or function in the general population. Five intronic single nucleotide polymorphisms (SNPs) were genotyped using the 5'-exonuclease activity (TaqMan) assay in the echocardiographic substudy of the third MONICA Augsburg survey. As ACE2 is located on the X chromosome, women and men were analysed separately. Four SNPs showed high pairwise linkage disequilibrium (rs4646156, rs879922, rs4240157 and rs233575). The minor alleles of these four SNPs were associated with higher left ventricular mass index (LVMI) and higher septal wall thickness (SWT) in men. Likewise, male carriers of a common haplotype (frequency 29.9%) consisting of the minor alleles of these four SNPs displayed higher values for LVMI and SWT than non-carriers (LVMI: TGGC 98.8+/-1.52 vs non-TGGC 94.8+/-0.99 g/m(2), p=0.027; SWT: TGGC 11.5+/-0.14 vs non-TGGC 11.1+/-0.09 mm, p=0.019). Furthermore, this haplotype was associated with an increased odds ratio (OR) for left ventricular hypertrophy (OR 3.10, p=0.006). In women, similar but less pronounced and consistent trends were observed. No association was observed between any of these SNPs and parameters of left ventricular systolic or diastolic function nor with blood pressure levels. This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, SWT and left ventricular hypertrophy in hemizygous men.

Association study of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms and essential hypertension in northern Han Chinese

“…The MAF differences may be owing to founder effect or genetic drift. Furthermore, the SNPs studied have similar MAFs in our study and in Chiu et al's study 10 and in the study of Lieb et al 5 (except rs2285666), but not in the study by Benjafield et al 4 (with relatively small sample), suggesting Chinese and Caucasian populations roughly have similar MAFs, respectively.…”

“…6,10 For rs1978124 and rs2285666, the MAF in Chinese Population is much higher than that in Australian and German populations. [4][5][6]10 For rs879922, the MAF in Australians is as high as 0.42 in females and 0.31 in males, and up to 0.36 in females and 0.33 in males in Germans, but it was lower than 0.05 in our study. The MAF differences may be owing to founder effect or genetic drift.…”

“…K Benjafield et al 4 found that there was no association between four ACE2 gene polymorphisms and hypertension in an Australian population of white Anglo-Celtic origin, and that the four SNPs studied were in LD. Similarly, Lieb et al 5 reported that five ACE2 SNPs were not associated with systolic or diastolic BP or pulse pressure in German subjects. K Recently, Zhong et al 6 showed that the ACE2 A/C polymorphism (rs2285666) is associated with hypertension in female Chinese patients with metabolic syndrome.…”

“…Benjafield et al 4 demonstrated that rs1978124, rs2285666, rs879922 and rs714205 (intron 16) were in LD (D 0 ¼ 0.54-1, P ¼ 0.05-0.001). Recently, Lieb et al 5 showed that rs4646156 (intron 8), rs879922, rs4240157 (intron 14) and rs233575 (intron 16), but not rs2285666, were in LD. Taken together, the strong LD and the similar MAFs of the studied SNPs suggest that the ACE2 region has both a low mutation rate and a low recombination rate, implying that this genomic region is very stable.…”

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

“…Interestingly, Apelin knockout mice showed aging-or stressassociated cardiac contractility defects, similar to the heart phenotype of ACE2 knockout mice, 60 suggesting that ACE2 and Apelin may share the same signaling pathway to control heart functions. Although further studies are required to validate the proposed crosstalk, in humans both ACE2 and Apelin polymorphisms are associated with parameters of left ventricular hypertrophy 61 and BP responses to potassium supplementation, 62 and soluble ACE2 activity is increased in patients with myocardial dysfunction and correlates with disease severity, 63 implicating physiological roles of ACE2 and Apelin in patients.…”