Influence of Angiotensin-converting Enzyme Insertion/Deletion Gene Polymorphism in Progression of Chagas Heart Disease

Abstract INTRODUCTION: Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi. One-third of infected patients will develop the cardiac form, which may progress to heart failure (HF). However, the factors that determine disease progression remain unclear. Increased angiotensin II activity is a key player in the pathophysiology of HF. A functional polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with plasma enzyme activity. In CD, ACE inhibitors have beneficial effects supporting the use of this treatment in chagasic cardiomyopathy. METHODS: We evaluated the association of ACE I/D polymorphism with HF, performing a case-control study encompassing 343 patients with positive serology for CD staged as non-cardiomyopathy (stage A; 100), mild (stage B1; 144), and severe (stage C; 99) forms of Chagas heart disease. For ACE I/D genotyping by PCR, groups were compared using unconditional logistic regression analysis and adjusted for nongenetic covariates: age, sex, and trypanocidal treatment. RESULTS: A marginal, but not significant (p=0.06) higher prevalence of ACE I/D polymorphism was observed in patients in stage C compared with patients in stage A. Patients in stage C (CD with HF), were compared with patients in stages A and B1 combined into one group (CD without HF); DD genotype/D carriers were prevalent in the HF patients (OR = 2; CI = 1.013.96; p = 0.04). CONCLUSIONS: Our results of this cohort study, comprising a population from the Northeast region of Brazil, suggest that ACE I/D polymorphism is more prevalent in the cardiac form of Chagas disease with HF.

The ACE I/D polymorphism is associated with nitric oxide metabolite and blood pressure levels in healthy Mexican men / El polimorfismo I/D de la ECA se asocia con los niveles de metabolitos óxido nítrico y de presión arterial en hombres mexicanos sanos

The I/D insertion/deletion polymorphism of the angiotensin-converting enzyme has been related to hypertension. This polymorphism also seems to have gender related implications. Angiotensin II contributes to the production and release of oxygen reactive species that react with nitric oxide, inactivating its effects. Objective: To establish whether the ACE I/D polymorphism correlates with nitric oxide plasma metabolites in healthy men and women. Methods: Among 896 subjects between 18 and 30 years of age range, 138 fulfilled inclusion criteria. The polymorphism was identified by polymerase chain reaction, and blood nitric oxide metabolites were analyzed following the method described by Bryan. Results: Both systolic and diastolic arterial pressures were higher in men than in women (107/67 vs. 101/65 mmHg, p < 0.001). In terms of the ACE gene, there were differences in the concentration of nitric oxide metabolites in men with the I/D and D/D genotypes when compared to carriers of the I/I genotype (33.55 and 29.23 vs. 53.74 pmol/ml; p = <0.05), while there were no significant differences in women when compared by genotype. Men with the D/D genotype had higher systolic blood pressure than I/D carriers (111 vs. 104 mmHg, p < 0.05). We observed no arterial blood pressure differences in women when grouped by ACE genotype. Conclusions: The ACE D/D genotype was associated with nitric oxide metabolite levels and systolic blood pressure in clinically healthy men while it had no effect in women.

El polimorfismo inserción/deleción del gen de la enzima convertidora de la angiotensina (polimorfismo I/D de la ECA), se relaciona con hipertensión y sus efectos podrían estar asociados al género. La angiotensina II contribuye a la producción y liberación de especies reactivas de oxígeno, que reaccionan con el óxido nítrico (ON), inactivándolo. Objetivo: Conocer si existen diferencias en la concentración de metabolitos de ON en hombres y mujeres sanos que puedan estar influidas por el polimorfismo I/D de la ECA. Métodos: De 896 sujetos de entre 18 y 30 años, 138 cumplieron los criterios de inclusión. El polimorfismo fue identificado usando reacción en cadena de la polimerasa y los metabolitos de ON fueron analizados en sangre usando el método de Bryan. Resultados: Las presiones sistólica y diastólica fueron más elevadas en hombres que en mujeres (107/67 vs. 101/65 mmHg p < 0.001). En relación con el genotipo, existieron diferencias significativas en la concentración de metabolitos de ON en los hombres con genotipos I/D, D/D comparados con los portadores del genotipo I/I (33.55 y 29.23 vs. 53.74 pmol/ml, respectivamente; p = <0.05). No hubo diferencias significativas en las mujeres portadoras de los diferentes genotipos. Respecto a la presión arterial, los hombres con genotipo D/D presentaron mayor presión arterial sistólica que aquellos portadores de I/D (111 vs. 104 mmHg, p < 0.05). En las mujeres no se observaron diferencias significativas comparándolas por genotipo. Conclusiones: El genotipo D/D de la ECA está asociado con el nivel de metabolitos de ON en plasma y la presión arterial sistólica en hombres clínicamente sanos; esta asociación no se observa en las mujeres.

Angiotensin-I-Converting Enzyme (ACE) Insertion/Deletion Polymorphism in Egyptian Patients with Coronary Artery Disease.

Angiotensin-I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been associated with the genetic susceptibility to coronary artery disease (CAD) and also with the lipid profile in different populations. One hundred and eight Egyptian patients with CAD and one hundred forty three unrelated healthy subjects were included in the study. ACE I/D polymorphism was detected by polymerase chain reaction. We investigated the association between I/D polymorphism of the ACE gene and the presence of CAD as well as its association with hypertension in the patients. Serum levels of lipoprotein (a), Lp (a), and interleukin-6 (IL-6) were estimated in the patients as well as in the healthy subjects. Increased frequency of D allele and DD genotype as well as decreased frequency of I allele and ID genotype were found in CAD patients compared to healthy subjects (P = .004, OR= 0.419, 95% CI (.2 - .8), for DD genotype), (P = .008, OR= 0.475, 95% CI (0.27- 0.84), for D allele). Higher levels of both Lp (a) and IL-6 were observed in CAD patients compared to control subjects (P = .0012, P = .0346, respectively). No association was observed in ACE gene polymorphism with diabetes mellitus or hyperlipidemia. However, there is a trend for DD genotype to develop more hypertension than ID genotype (P=0.08, OR=2.88). In conclusion, theI/D polymorphism of the ACE gene (carrying the D allele) is an independent risk factor for CAD in the studied Egyptian population.

Null association between ACE gene I/D polymorphism and diabetic nephropathy among multiethnic Malaysian subjects.

BACKGROUND: Wide inter-ethnic allelic variations of the Angiotensin Converting Enzyme (ACE) i nsertion-deletion (I/D) gene polymorphism were thought to be responsible for the conflicting gene–diabetic nephropathy disease association worldwide. We have investigated the genetic susceptibility of the ACE gene to diabetic nephropathy in the multiethnic Malaysian population. MATERIALS AND METHODS: A total of 137 healthy (control) and 256 diabetic subjects were recruited. The diabetic subjects were further subdivided according to their nephropathy status based on urinary albumin-creatinine ratio (ACR) and glomerular filtration rate (GFR). Triple primer polymerase chain reaction (PCR) was used for ACE I/D genotyping. Subsequently, populationwide genetic analysis and gene-disease association studies were performed. RESULTS: The genotype frequencies in all subgroups were in Hardy-Weinberg equilibrium. Similar allelic and genotypic frequency of ACE I/D gene polymorphism was observed between healthy controls versus pooled type 2 diabetes mellitus (T2DM) subjects, and normoalbuminuria versus microalbuminuria, macroalbuminuria and End Stage Renal Failure (ESRF) (P > 0.05). Neither ethnicity nor gender exerted any influence on the ACE I/D gene polymorphism (P > 0.05), with the exception of the Chinese ethnic group which exhibited a higher frequency of ID genotype (P = 0.042). A multinomial logistic regression model showed that predictive factors including age, systolic blood pressure (SBP), high density lipoprotein (HDL) and glycosylated hemoglobin (HbA1C) were independently associated with diabetic nephropathy, in that order. CONCLUSION: The I/D polymorphism of the ACE gene is not significantly associated with both T2DM and/or diabetic nephropathy in this Malaysian population regardless of ethnicity and gender.

Correlación del polimorfismo (I/D) del gen de la ECA y la función ventricular en pacientes con miocardiopatía dilatada de origen isquémico e idiopático / ACE gene polymorphysm correlation (I/D) with the ventricular function in patients with ischemic and dilate idiopathic cardiomyopathy

Dilated cardiomyopathy is a myocardial disease, characterized by biventricular expansion. Renin-angiotensin-aldosterone system (RAAS) is closely related with the progress of this pathology. Has been shown that angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influences as much in the plasmatic concentration as in activity of ACE. In addition, ACE I/D polymorphism has been associated with remodeling phenomena and an increased risk to develop several cardiovascular diseases. On virtue of the influence of ACE gene polymorphism on RAAS, we studied the correlation between ACE I/D polymorphism with morphologic and functional clinical alterations in ischemic or idiopathic dilated cardiomyopathy in one attempt to establish its utility as prognosis factor. Methods and results. We studied 30 patients of The National Institute of Cardiology. Ventricular function was evaluated by transthoracic echocardiography. ACE genotype was determined by polymerase chain reaction (PCR). Results for left ventricle shown: Tei Index was increased in patients with II genotype (0.84 vs. 0.48) when were compared to patients with DD genotype p < 0.01. Eccentricity Index was lesser in the group with II genotype (0.64), than in the group DD (0.86) p < 0.01. Ventricular mass was increased in DD patients when was compared with II group (174 g vs. 133 g) Isovolumetric contraction time was shorter in group DD than in II (45 mseg vs. 139 mseg) p < O.OB. These findings denote better preservation of left ventricular function in patients with DD genotype. In opposition, right ventricle shown an increased Tei Index in the group with DD genotype (1.01) when was compared with II genotype (0.55), p < 0.05. Pulmonary artery systolic pressure tended to be higher in DD genotype group without reach statistic significance. Conclusions. In our group of study, patients with DD genotype shown better left ventricular function in ischemia or idiopathic dilated cardiomyopathy. On the opposite right ventricular function were more deteriorated in patients with ACE DD genotype.

La miocardiopatía dilatada es una enfermedad primaria del miocardio, caracterizada por dilatación biventricular. El sistema renina-angiotensina-aldosterona (SRAA) está estrechamente relacionado con el progreso de esta patología. Se ha demostrado que el polimorfismo inserción/deleción (I/D) del gen de la enzima convertidora de angiotensina (ECA) influye en la concentración plasmática y la actividad de esta enzima, además este polimorfismo se ha asociado con fenómenos de remodelación e incremento en el riesgo de padecer diferentes enfermedades cardiovasculares. En virtud de la influencia de las variantes polimórficas del gen de la ECA sobre la respuesta del SRAA, en el presente trabajo se estudió la posible correlación del polimorfismo I/D del gen de la ECA con las alteraciones clínicas morfológicas y funcionales de la cardiomiopatía dilatada tanto de origen isquémico como de origen idiopático con el fin de establecer su posible utilidad como factor pronóstico. Métodos y resultados. El estudio incluyó a 30 pacientes seleccionados de la consulta externa del Instituto Nacional de Cardiología <>, la función ventricular se valoró mediante ecocardiografía transtorácica. El genotipo de la ECA se determinó por reacción en cadena de la polimerasa (PCR). Resultados para el ventrículo izquierdo: El índice de Tei se observó visiblemente incrementado en los pacientes con genotipo II 0.84 vs. 0.48 de los pacientes con genotipo DD p < 0.01. El índice de excentricidad fue menor en los casos con genotipo II: 0.64, comparado con aquellos con genotipo DD: 0.86 p < 0.01. La masa ventricular tendió a ser mayor en el grupo DD en relación con el II (174 g vs. 133 g). El tiempo de contracción isovolumétrica fue menor en el grupo DD en comparación al II (45 mseg vs. 139 mseg) p < 0.05, estos hallazgos denotan una mejor preservación de la función ventricular izquierda en los pacientes con genotipo DD. Por otra parte, el ventrículo derecho mostró un comportamiento distinto al observado para el ventrículo izquierdo, pues el índice de Tei fue mayor para los pacientes con el genotipo DD (1.01) comparado con el grupo del genotipo II (0.55), p < 0.05. La presión sistólica de la arteria pulmonar tendió a ser mayor en los pacientes con genotipo DD sin alcanzar una significancia estadística. Conclusión. El genotipo DD se asocia con una mejor función ventricular izquierda en los pacientes con miocardiopatía dilatada de origen tanto isquémico como idiopático; por el contrario, la función ventricular derecha de los pacientes con genotipo DD muestra una mayor alteración en el índice de Tei en esta patología.