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Angiotensin-1 converting enzyme I/D gene polymorphism: scenario in Malaysia

Jayapalan JJ, Muniandy S, Chan SP

Southeast Asian J. Trop. Med. Public Health, 2008 Sep;39(5):917-21.
PMID: 19058590

Discrepancies in angiotensin-1 converting enzyme (ACE) allele genetic susceptibility with disease etiology have been attributed to ethnic differences. We investigated ACE gene polymorphism of the multiethnic Malaysian population by utilizing nested polymerase chain reaction. Allelic frequency of 0.65 and 0.35 for I and D allele, respectively in the pooled population was comparable with other Asian populations. A significant association was found between the Malaysian ethnic groups and ACE I/D genotype. The II genotype was found at higher frequency among the Malays but a greater frequency of DD genotype among Indians.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*
Fulltext Angiotensin-converting enzyme gene I/D dimorphism does not play a major role in the susceptibility of Malaysian systemic lupus erythematosus patients

Lian LH, Lau TP, Ching AS, Chua KH

Genet. Mol. Res., 2012;11(2):863-71.
PMID: 22576914 DOI: 10.4238/2012.April.10.2

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes systemic damage, involving auto-reactive antibodies and over-deposition of immune complexes. Susceptibility to SLE is believed to be multifactorial, and genetics is one of the proven etiological factors; it can affect SLE development, severity and prognosis. We investigated a possible association between the angiotensin-converting enzyme gene and susceptibility to SLE in the Malaysian population. PCR was employed for the determination of I/D dimorphism of this gene. The I allele was more frequent than the D allele in both the SLE patients (N = 170) and healthy controls (N = 190). However, there was no significant difference in the distribution of these two alleles between both groups studied (χ(2) = 0.284, P > 0.05). Interestingly, the DD homozygous genotype scored notably higher in the healthy control group (χ(2) = 7.568, P < 0.05), while the ID heterozygote was observed to be significantly associated with SLE (χ(2) = 11.143, P < 0.05). In conclusion, with respect to the Malaysian population, the DD genotype might play a protective role in the development of SLE while in contrast, those who carry the ID genotype might be at potential risk for onset of this disease.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*
Fulltext SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals

Lam SD, Bordin N, Waman VP, Scholes HM, Ashford P, Sen N, et al.

Sci Rep, 2020 Oct 05;10(1):16471.
PMID: 33020502 DOI: 10.1038/s41598-020-71936-5

SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics
Fulltext Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

Joyce-Tan SM, Zain SM, Abdul Sattar MZ, Abdullah NA

J Diabetes Res, 2016;2016:2161376.
PMID: 26682227 DOI: 10.1155/2016/2161376

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics
Signaling pathway genes for blood pressure, folate and cholesterol levels among hypertensives: an epistasis analysis

Wei LK, Menon S, Griffiths LR, Gan SH

J Hum Hypertens, 2015 Feb;29(2):99-104.
PMID: 25055800 DOI: 10.1038/jhh.2014.53

Irregular atrial pressure, defective folate and cholesterol metabolism contribute to the pathogenesis of hypertension. However, little is known about the combined roles of the methylenetetrahydrofolate reductase (MTHFR), apolipoprotein-E (ApoE) and angiotensin-converting enzyme (ACE) genes, which are involved in metabolism and homeostasis. The objective of this study is to investigate the association of the MTHFR 677 C>T and 1298A>C, ACE insertion-deletion (I/D) and ApoE genetic polymorphisms with hypertension and to further explore the epistasis interactions that are involved in these mechanisms. A total of 594 subjects, including 348 normotensive and 246 hypertensive ischemic stroke subjects were recruited. The MTHFR 677 C>T and 1298A>C, ACE I/D and ApoEpolymorphisms were genotyped and the epistasis interaction were analyzed. The MTHFR 677 C>T and ApoE polymorphisms demonstrated significant associations with susceptibility to hypertension in multiple logistic regression models, multifactor dimensionality reduction and a classification and regression tree. In addition, the logistic regression model demonstrated that significant interactions between the ApoE E3E3, E2E4, E2E2 and MTHFR 677 C>T polymorphisms existed. In conclusion, the results of this epistasis study indicated significant association between the ApoE and MTHFR polymorphisms and hypertension.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*
Renin-Angiotensin-Aldosterone System Gene Polymorphisms and Type 2 Diabetic Nephropathy in Asian Populations: An Updated Meta-analysis

Ahmad N, Jamal R, Shah SA, Gafor AHA, Murad NAA

Curr Diabetes Rev, 2019;15(4):263-276.
PMID: 29984662 DOI: 10.2174/1573399814666180709100411

BACKGROUND: The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D), Angiotensinogen (AGT) M235T and Angiotensin II Receptor Type 1 (AGTR1) A1166C with Diabetic Nephropathy (DN) has been studied for decades.
OBJECTIVE: This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus.
METHODS: The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration.
RESULTS: In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (≥10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model).
CONCLUSION: In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics
Fulltext The effects of angiotensin-converting enzyme gene polymorphism on the progression of immunoglobulin A nephropathy in Malaysian patients

Draman CR, Kong NC, Gafor AH, Rahman AF, Zainuddin S, Mustaffa WM, et al.

Singapore Med J, 2008 Nov;49(11):924-9.
PMID: 19037561

Angiotensin-converting enzyme (ACE) gene polymorphism, especially the deletion/deletion (DD) genotype, is associated with the disease progression of immunoglobulin A (IgA) nephropathy patients in various studies from both Asia Pacific and European populations. However, recent studies within the same populations were unable to reproduce the same results. Hence, we had studied the distribution of the DD genotype, the association between ACE gene polymorphism and the disease progression, and the factors (other than ACE gene polymorphism) which were involved in the disease progression of our local patients.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*
Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene with essential hypertension and type 2 diabetes mellitus in Malaysian subjects

Ramachandran V, Ismail P, Stanslas J, Shamsudin N, Moin S, Mohd Jas R

J Renin Angiotensin Aldosterone Syst, 2008 Dec;9(4):208-14.
PMID: 19126661 DOI: 10.1177/1470320308097499

The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene has been studied in various populations in relation to hypertension (HTN) and type 2 diabetes mellitus (T2DM) with contradictory results. This study sought to determine the association of insertion (I)/D polymorphism of the ACE gene in hypertensive and T2DM subjects in a Malaysian population.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*
Clinical Relevance of MTHFR, eNOS, ACE, and ApoE Gene Polymorphisms and Serum Vitamin Profile among Malay Patients with Ischemic Stroke

Wei LK, Au A, Menon S, Gan SH, Griffiths LR

J Stroke Cerebrovasc Dis, 2015 Sep;24(9):2017-25.
PMID: 26187788 DOI: 10.1016/j.jstrokecerebrovasdis.2015.04.011

The purpose of this study was threefold. First, it was to determine the relationship between serum vitamin profiles and ischemic stroke. The second purpose was to investigate the association of methylenetetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and apolipoprotein-E (ApoE) gene polymorphisms with ischemic stroke and further correlate with serum vitamin profiles among ischemic stroke patients. The third purpose of the study was to highlight the interaction of MTHFR and eNOS haplotypes with serum vitamin profiles and ischemic stroke risks.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*
Fulltext Arthropod Ectoparasites Have Potential to Bind SARS-CoV-2 via ACE

Lam SD, Ashford P, Díaz-Sánchez S, Villar M, Gortázar C, de la Fuente J, et al.

Viruses, 2021 04 19;13(4).
PMID: 33921873 DOI: 10.3390/v13040708

Coronavirus-like organisms have been previously identified in Arthropod ectoparasites (such as ticks and unfed cat flea). Yet, the question regarding the possible role of these arthropods as SARS-CoV-2 passive/biological transmission vectors is still poorly explored. In this study, we performed in silico structural and binding energy calculations to assess the risks associated with possible ectoparasite transmission. We found sufficient similarity between ectoparasite ACE and human ACE2 protein sequences to build good quality 3D-models of the SARS-CoV-2 Spike:ACE complex to assess the impacts of ectoparasite mutations on complex stability. For several species (e.g., water flea, deer tick, body louse), our analyses showed no significant destabilisation of the SARS-CoV-2 Spike:ACE complex, suggesting these species would bind the viral Spike protein. Our structural analyses also provide structural rationale for interactions between the viral Spike and the ectoparasite ACE proteins. Although we do not have experimental evidence of infection in these ectoparasites, the predicted stability of the complex suggests this is possible, raising concerns of a possible role in passive transmission of the virus to their human hosts.

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics
Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors

Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, Etemad A, Pishva SR, et al.

J Renin Angiotensin Aldosterone Syst, 2015 Dec;16(4):872-9.
PMID: 25002132 DOI: 10.1177/1470320314538878

Several studies show that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with hypertension in various populations. The present study sought to determine the association of the I/D gene polymorphism among Malay male essential hypertensive subjects in response to ACE inhibitors (enalapril and lisinopril).

Matched MeSH terms: Peptidyl-Dipeptidase A/genetics*