Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia GbpWYDbszHBzvcpYCdRMkCK S0066-782X2014002300012 00012 10.5935/abc.20140182 Letter to the Editor ACE I/D Gene Polymorphism in Children with Family History of Premature Coronary Disease Yý lmaz Çiftdoð an Dilek Ý zmir Tepecik Training and Research Hospital Turquia Ý zmir Tepecik Training and Research Hospital, Turquia Mailing Address: Dilek Yý lmaz Çiftdoð an. Ý zmir Tepecik Training and Research Hospital, Department of Pediatrics, Ý zmir. Postal Code: 35100, Ý Zmir - Turquia. Email: drdilekyilmaz@hotmail.com 11 2014 103 5 440 442 22 07 2014 28 08 2014 28 08 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Polymorfism, Genetic Peptidyl-Dipeptidase A Coronary Artery Disease Child

Letter to the editor regarding the article by de Albuquerque et al: Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling.

I read with interest the recent review article by de Albuquerque et al1 published in the Arquivos Brasileiros de Cardiologia entitled “Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling.” They showed that the DD genotype of Angiotensin-converting enzyme (ACE) gene polymorphism was independently associated with worse echocardiographic outcome, while the DI genotype, with the best echocardiographic profile1.

Atherosclerosis, the major cause of CAD, manifests clinically in adulthood. However, this disease begins very early in life, often during childhood. Genetic and environmental factors, gene–environment interaction effects also come into play in the development of atherosclerosis. Family history is the most significant independent risk factor for CAD.

In our study, we included a total of 140 children, 72 males and 68 females between the ages of 4.9 and 15.7 years. Among these children, 73 had a parental history of premature CAD (parents have been diagnosed with the CAD by coronary angiographic study, ages below 55 for men and 65 for women) and the rest of 67 belonged to our control group (parents have shown normal coronary angiographic study). The participants were screened for the mutations ACE I/D gene polymorphisms.

The genotypes of ACE I/D were significantly different between the study and control groups (p = 0.01). The frequency of D/D genotype was significantly higher in the study group than the control group (respectively, 20/73 vs. 3/67, p = 0.01) (Table 1). The frequency of the D allele was slightly higher in study group (0.52) than in control group (0.27) (p = 0.005).

The frequencies of the ACE I/D gene polymorphisms in study group and control group, and the odds ratios with 95% CI
Genetic polymorphism Study group (Children whose parents with premature CAD) n (%) Control group (Children whose parents without premature CAD) n (%) p Value Odds Ratios (CI 95%)
ACE        
D/D 20 (27.4%) 3 (4.4%) 0.01 2.98 (1.12 - 6.82)1
D/I 37 (50.6%) 30 (44.6%)
I/I 16 (21.9%) 34 (50.0%)

: D/D versus I/D and I/I.

The angiotensin converting enzyme is a key factor in the production of angiotensin II and in the degradation of bradykinin. Chronic exposure to high levels of circulating and tissue ACE predispose to vascular wall thickening and atherosclerosis. The ACE insertion/deletion (I/D) polymorphism results from the absence or presence of an alu repeat located in intron 16 of the ACE gene. The D allele of an insertion/deletion (I/D) polymorphism of the gene encoding ACE is associated with higher plasma ACE concentrations2. Many studies have investigated the association between the DD genotype of ACE gene I/D polymorphic variant and CAD3,4. However, these outcomes have not been supported by the other studies5. In present study, the frequencies of D/D genotype and D allel of ACE gene considerably higher in children with parental history of premature CAD than control group.

We showed that the frequencies of the DD genotype and the D allel of ACE I/D gene polymorphism are higher in children with parental history of premature CAD. This results may be associated with an increased risk for development of atherosclerosis. It may be contribute to the detection of the risk of children with a parental history of CAD. Thus, further large population studies must be done to confirm this results.

The study protocol was approved by the Local Ethical Committee of Celal Bayar University, and informed written consent was obtained from all participants. This study was funded by Celal Bayar University.

Additional information:

In addition to ACE I/D gene polymorphism, glycoprotein IIIa, factor V G1691A, factor V H1299R, prothrombin G20210A and apolipoprotein E polymorphism had been investigated in the same study group. These results were published in various journals.

* Ciftdoğan DY. Glycoprotein IIIa gene polymorphism in children with a family history of premature coronary artery disease. Acta Cardiol. 2010 Dec;65(6):695; author reply 695-6.

** Ciftdoğan DY, Coşkun S, Ulman C, Tikiz H. The factor V G1691A, factor V H1299R, prothrombin G20210A polymorphisms in children with family history of premature coronary artery disease. Coron Artery Dis. 2009 Nov;20(7):435-9. doi: 10.1097/MCA.0b013e32832bdb8c.

*** Ciftdoğan DY, Coskun S, Ulman C, Tıkız H. The association of apolipoprotein E polymorphism and lipid levels in children with a family history of premature coronary artery disease. J Clin Lipidol. 2012 Jan-Feb;6(1):81-7. doi: 10.1016/j.jacl.2011.06.017. Epub 2011 Jul 30.

 References de Albuquerque FN, Brandão AA, da Silva DA, Mourilhe-Rocha R, Duque GS, Gondar AF, et al. Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling. Arq Bras Cardiol. 2014;102(1):70-9. de Albuquerque FN Brandão AA da Silva DA Mourilhe-Rocha R Duque GS Gondar AF et al Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling Arq Bras Cardiol 2014 102 1 70 79 Sobti RC, Maithil N, Thakur H, Sharma Y, Talwar KK. Association of ACE and Factor VII gene variability with the risk of coronary heart disease in north Indian population. Mol Cell Biochem. 2010;341(1-2):87-98. Sobti RC Maithil N Thakur H Sharma Y Talwar KK Association of ACE and Factor VII gene variability with the risk of coronary heart disease in north Indian population Mol Cell Biochem 2010 341 1-2 87 98 Beohar N, Damaraju S, Prather A, Yu QT, Raizner A, Kleiman NS, et al. Angiotensin-I converting enzyme genotype DD is a risk factor for coronary artery disease. J Investig Med. 1995;43(3):275-80. Beohar N Damaraju S Prather A Yu QT Raizner A Kleiman NS et al Angiotensin-I converting enzyme genotype DD is a risk factor for coronary artery disease J Investig Med 1995 43 3 275 280 Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359(6396):641-4. Cambien F Poirier O Lecerf L Evans A Cambou JP Arveiler D et al Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction Nature 1992 359 6396 641 644 Shafiee SM, Firoozrai M, Salimi S, Zand H, Hesabi B, Mohebbi A. Angiotensin converting enzyme DD genotype not associated with increased risk of coronary artery disease in the Iranian population. Pathophysiology. 2010;17(3):163-7. Shafiee SM Firoozrai M Salimi S Zand H Hesabi B Mohebbi A Angiotensin converting enzyme DD genotype not associated with increased risk of coronary artery disease in the Iranian population Pathophysiology 2010 17 3 163 167 Reply

The insertion1 /deletion (I/D) polymorphism in the gene for angiotensin converting enzyme (ACE) has been studied in different clinical scenarios beyond heart failure (HF), which is described in this article, such as hypertension1, atrial fibrillation (AF)2, and coronary heart disease (CHD)3. In all these scenarios, there appears to be a relationship between the DD genotype and poor clinical outcome, albeit with some controversy due to the small number of patients.

Typically, the outcomes used in these small studies are surrogate markers such as echocardiographic parameters (original article) or left ventricular hypertrophy1, for example. In other works, it is only possible to detect the relationship between genotypes and incidence of the disease studied2.

In the case of atherosclerosis, because of the prevalence and importance of CHD, there are a greater number of publications such as those presented in letters to the editor on the various types of atherosclerosis: subclinical or clinical. Our work4, in particular, focused only on patients with nonischemic HF, and it was possible to observe the association between poor Echo profile and the DD genotype.

More recently, it has been described tha HF physiopathology and Renin Angiotensin activity is actually linked to a polygenic heritage. The simultaneous study of multiple genetic polymorphisms (GPs) in the same population has identified that only combinations of genotypes have been associated with clinical and/or echocardiographic outcomes5,6.

Therefore, it is likely that a panel of genetic markers would be more efficient in detecting more severely ill individuals than isolated GPs. Since then, our group has been focusing on this kind of analysis, and preliminary data suggest an association between a genetic panel, which included polymorphisms of the angiotensin-converting enzyme, beta adrenergic receptor type 1, nitric oxide synthetase, and Angiotensin II, and clinical outcomes. The continuation of this study, which is already underway, with more patients may help clarify this issue.

Sincerely,

Felipe Neves de Albuquerque, Andréa Araujo Brandão, Dayse Aparecida da Silva, Ricardo Mourilhe-Rocha, Gustavo Salgado Duque, Alyne Freitas Pereira Gondar, Luiza Maceira de Almeida Neves, Marcelo Imbroinise Bittencourt, Roberto Pozzan, Denilson Campos de Albuquerque

References Pontremoli R, Sofia A, Tirotta A, Ravera M, Nicolella C, Viazzi F, et al. The deletion polymorphism of the angiotensin I-converting enzyme gene is associated with target organ damage in essential hypertension. Am Soc Nephrol. 1996;7(12):2550-8. Pontremoli R Sofia A Tirotta A Ravera M Nicolella C Viazzi F et al The deletion polymorphism of the angiotensin I-converting enzyme gene is associated with target organ damage in essential hypertension Am Soc Nephrol 1996 7 12 2550 2558 Topal NP, Ozben B, Hancer VS, Tanrikulu AM, Diz-Kucukkaya R, Fak AS, et al. Polymorphisms of the angiotensin-converting enzyme and angiotensinogen gene in patients with atrial fibrillation. J Renin Angiotensin Aldosterone Syst. 2911;12(4):549-56. Topal NP Ozben B Hancer VS Tanrikulu AM Diz-Kucukkaya R Fak AS et al Polymorphisms of the angiotensin-converting enzyme and angiotensinogen gene in patients with atrial fibrillation J Renin Angiotensin Aldosterone Syst 2911 12 4 549 556 Mutthumala A, Montgomery H, Palmen J, Cooper JA, Humphries SE. Angiotensin-converting enzyme genotype interacts with systolic blood pressure to determine coronary heart disease risk in healthy middle-aged men. Hypertension. 2007;50(2):348-53. Mutthumala A Montgomery H Palmen J Cooper JA Humphries SE Angiotensin-converting enzyme genotype interacts with systolic blood pressure to determine coronary heart disease risk in healthy middle-aged men Hypertension 2007 50 2 348 353 Albuquerque FN de, Brandão AA, Silva DAD, Mourilhe-Rocha R, Duque GS, Gondar AF, et al. Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling. Arq Bras Cardiol. 2014;102(1):70-9. Albuquerque FN de Brandão AA Silva DAD Mourilhe-Rocha R Duque GS Gondar AF et al Angiotensin-converting enzyme genetic polymorphism: its impact on cardiac remodeling Arq Bras Cardiol 2014 102 1 70 79 Zakrzewski-Jakubiak M, de Denus S, Dubé M-P, Bélanger F, White M, Turgeon J. Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Caucasian patients with heart failure. Br J Clin Pharmacol. 2006;5(5):742-51. Zakrzewski-Jakubiak M de Denus S Dubé M-P Bélanger F White M Turgeon J Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Caucasian patients with heart failure Br J Clin Pharmacol 2006 5 5 742 751 Kitsios G, Zintzaras E. Genetic variation associated with ischemic heart failure: a huge review and meta-analysis. Am J Epidemiol. 2007;116(6):619-33. Kitsios G Zintzaras E Genetic variation associated with ischemic heart failure: a huge review and meta-analysis Am J Epidemiol 2007 116 6 619 633 Carta ao Editor Polimorfismo I/D do Gene da ECA em Crianças com Histórico Familiar de Doença Arterial Coronariana Prematura Yý lmaz Çiftdoð an Dilek Ý zmir Tepecik Training and Research Hospital Turquia Ý zmir Tepecik Training and Research Hospital, Turquia Correspondência: Dilek Yý lmaz Çiftdoð an. Ý zmir Tepecik Training and Research Hospital, Department of Pediatrics, Ý zmir. Código postal: 35100, Ý Zmir - Turquia. Email: drdilekyilmaz@hotmail.com

Carta ao editor relativo ao artigo de Albuquerque et al.: Impacto do polimorfismo genético da enzima conversora da angiotensina no remodelamento cardíaco.

Li com interesse a revisão publicada recentemente nos Arquivos Brasileiros de Cardiologia por Albuquerque e cols1. intitulada “Impacto do polimorfismo genético da enzima conversora da angiotensina no remodelamento cardíaco”. Nesta revisão, foi mostrado que o genótipo DD da enzima conversora da angiotensina (ECA) está associado de forma independente à pior evolução cardiográfica e o genótipo DI está associado ao melhor perfil cardiográfico1.

A arteriosclerose é a principal causa de doença arterial coronariana (DAC). Apesar de manifestar-se clinicamente na idade adulta, a DAC geralmente inicia-se na infância. Fatores genéticos e ambientais e efeitos da interação gene-ambiente influenciam o desenvolvimento da arteriosclerose, mas o histórico familiar é o fator de risco mais significante na incidência da DAC.

Em nosso estudo, 140 crianças foram avaliadas, dentre as quais 72 eram do sexo masculino e 68 do sexo feminino entre 4,9 e 15,7 anos de idade. Deste total, 73 crianças apresentaram histórico familiar de DAC prematura (pais foram diagnosticados com DAC através de angiografia coronária quando apresentaram idade inferior a 55 anos (homens) e 65 anos (mulheres)). As demais 67 crianças pertenciam ao grupo controle (pais com angiografia coronária normal). Os participantes foram avaliados quanto à presença do polimorfismo I/D no gene da ECA.

Os genótipos I/D da ECA foram significativamente diferentes entre os grupos experimental e controle (p = 0,01). A frequência do genótipo D/D foi significativamente superior no grupo experimental quando comparado ao grupo controle (20/73 vs. 3/67, respectivamente, p = 0,01) (Tabela 1). A frequência do alelo D foi ligeiramente superior no grupo experimental (0,52) quando comparado ao grupo controle (0,27) (p = 0,005).

Frequência do polimorfismo I/D do gene de ECA nos grupos experimental e controle. IC = 95%
Polimorfismo Genético Grupo experimental (Crianças cujos pais apresentaram DAC prematura) n (%) Grupo Controle (Crianças cujos pais não apresentaram DAC prematura) n (%) Valor de p Odds Ratio (IC 95%)
ECA        
D/D 20 (27,4%) 3 (4,4%) 0,01 2,98 (1,12 - 6,82)1
D/I 37 (50,6%) 30 (44,6%)
I/I 16 (21,9%) 34 (50,0%)

: D/D versus I/D and I/I.

A ECA é um fator importante não só na produção de angiotensina II como também na degradação de bradicinina. A exposição crônica a altos níveis de ECA, tanto na circulação como nos tecidos, está relacionada à predisposição para redução do calibre das artérias e desenvolvimento de arteriosclerose. O polimorfismo I/D da ECA resulta da presença (inserção–I) ou ausência (deleção–D) de uma repetição Alu localizada no íntron 16 do gene da ECA. O alelo D está associado ao aumento das concentrações plasmáticas de ECA2. Vários estudos investigaram a associação entre o genótipo D/D e o desenvolvimento de DAC3,4 , mas tal associação não foi confirmada por outros grupos5. Neste estudo, no entanto, observamos que a frequência do genótipo D/D e do alelo D do gene da ECA foram consideravelmente superiores em crianças com histórico familiar de DAC prematura quando comparadas ao grupo controle.

Além disso, mostramos que as frequências do genótipo DD e do alelo D do gene da ECA foram maiores em crianças com histórico familiar de DAC prematura. Estes resultados indicam maior risco de arteriosclerose nestes indivíduos e podem contribuir para o diagnóstico de crianças com risco de desenvolver DAC. Assim, estudos envolvendo populações maiores devem ser conduzidos para confirmação destes resultados.

Este estudo obteve suporte financeiro da Universidade de Celal Bayar e foi aprovado pelo Comitê de Ética em Pesquisa local da Universidade. Todos os participantes assinaram um Termo de Consentimento Livre e Esclarecido.

Informação adicional:

Além do polimorfismo I/D do gene da ECA, os polimorfismos dos genes da glicoproteína IIIa, mutações G1691A e H1299R do Fator V, e mutação G20210A da protrombina e apolipoproteína E também foram investigados pelo nosso grupo. Estes resultados foram publicados em diversos periódicos.

* Ciftdoğan DY. Glycoprotein IIIa gene polymorphism in children with a family history of premature coronary artery disease. Acta Cardiol. 2010;65(6):695.

** Ciftdoğan DY, Coşkun S, Ulman C, Tikiz H. The factor V G1691A, factor V H1299R, prothrombin G20210A polymorphisms in children with family history of premature coronary artery disease. Coron Artery Dis. 2009;20(7):435-9.

*** Ciftdoğan DY, Coskun S, Ulman C, Tıkız H. The association of apolipoprotein E polymorphism and lipid levels in children with a family history of premature coronary artery disease. J Clin Lipidol. 2012;6(1):81-7.

 Carta-resposta

O polimorfismo genético Inserção1 /Deleção (D) da ECA tem sido estudado em diferentes quadros clínicos além da insuficiência cardíaca (IC), incluindo hipertensão arterial (HA)1 , fibrilação arterial (FA)2 e doença arterial coronariana (DAC)3. Em todos estes casos, apesar da controvérsia quanto ao tamanho da amostra, tem-se observado uma associação entre o genótipo D/D e pior evolução clínica.

Os parâmetros avaliados nos estudos menores geralmente constituem marcadores substitutos, tais como variáveis ecocardiográficas (artigo original) ou hipertrofia ventricular esquerda1. Em outros casos, somente é possível estabelecer a relação entre genótipos e a incidência da doença2.

A arteriosclerose é um caso especial devido à alta prevalência e importância da DAC. Diferentes tipos de publicações estão disponíveis, envolvendo ensaios clínicos e não clínicos (incluindo a apresentada nesta carta). Em nosso estudo4 , entretanto, acompanhamos somente pacientes com insuficiência cardíaca não-isquêmica e pudemos observar uma associação entre o genótipo D/D e pior padrão ecocardiográfico.

Mais recentemente foi descrito que a fisiopatologia da IC e a atividade do sistema renina-angiotensina-aldosterona são determinados por herança poligênica. Um estudo de múltiplos polimorfismos genéticos em uma população mostrou que somente a combinação destes genótipos está significantemente associada à complicações clínicas e ecocardiográficas5,6.

Portanto, é provável que um painel de marcadores genéticos e não um polimorfismo genético isolado seja mais eficiente em diagnosticar indivíduos de alto risco. Assim, nosso grupo tem focado neste tipo de análise e resultados preliminares sugerem a associação de um painel genético (incluindo: enzima conversora da angiotensina, receptor beta adrenérgico 1, óxido nítrico sintase, polimorfismos da angiotensina II) e desfechos clínicos. Os resultados do presente estudo (em desenvolvimento) devem contribuir para elucidar este assunto.

Atenciosamente,

Felipe Neves de Albuquerque, Andréa Araujo Brandão, Dayse Aparecida da Silva, Ricardo Mourilhe-Rocha, Gustavo Salgado Duque, Alyne Freitas Pereira Gondar, Luiza Maceira de Almeida Neves, Marcelo Imbroinise Bittencourt, Roberto Pozzan, Denilson Campos de Albuquerque.