Impact of angiotensin-converting enzyme gene polymorphism on proteinuria and arterial hypertension [Utjecaj polimorfizma gena angiotenzin i konvertaze (ACE) na proteinuriju i arterijsku hipertenziju]

Živko, Marijana and Kušec, Rajko and Galešić, Krešimir (2013) Impact of angiotensin-converting enzyme gene polymorphism on proteinuria and arterial hypertension [Utjecaj polimorfizma gena angiotenzin i konvertaze (ACE) na proteinuriju i arterijsku hipertenziju]. Collegium Antropologicum, 37 (3). pp. 765-770. ISSN 0350-6134

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Abstract

Proteinuria is the hallmark of renal disease. In essential hypertension the onset of de novo proteinuria is associated with faster rate of progression of disease. Some authors have suggested that the DD genotype of the angiotensin-converting enzyme (ACE) gene would be an adverse renal prognosis factor. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. Observations on the association between the ACE gene polymorphism and hypertension have been inconsistent, which might be due to ethnic and geographical variations. In this study was to investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (ramipril) and to evaluate the possible association between I/D polymorphism and hypertension. We recruited 66 hypertensive patients (male 42, female 24) with overt proteinuria (urinary protein excretion over 500 mg/day). Patients were classified into three groups in accordance with ACE genotypes (17 DD; 35 ID; 14 II). They were treated with ramipril and prospectively followed up for one year. Various clinical parameters including age, body mass index (BMI), 24-h urine protein, creatinine, creatinine clearance (Ccr), systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP) were measured in the pre- and post-treatment periods. The ACE gene insertion/deletion(I/D) polymorphisms in intron 16 were determined by PCR. Results showed that there were no significant differences in the clinical parameters such as age, gender, serum creatinine, Ccr, SBP, DBP, MAP, and daily urinary excretion of protein among three groups (P > 0.05). ID genotype patients were found to have lower BMI (p = 0.031). ACE inhibition significantly reduced proteinuria in all genotype groups (p < 0.05). The percentage reductions of 24-h urinary excretion of protein were significantly different between the genotype groups (p = 0.042) and for DD genotype were significantly greater than in ID (79.2 +/- 28.9% vs 49.2 +/- 64.8%, P = 0.015). The slope of SBP was the main factor related to the slope of the percentage reduction of proteinuria, however, a significant negative correlation coefficient between these parameters was found (rs = -0.382, p = 0.002). We failed to find significant difference in outcomes of treatments with ACE inhibitor between male and female according the I/D polymorphism of the ACE gene. D allele in the ACE genotype could be a useful genetic marker with important clinical, therapeutic and prognostic implications in recognizing patients with proteinuria that are at greater risk of renal damage.

Abstract in Croatian

Proteinurija je najraniji znak oštećenja bubrega. U esencijalnoj hipertenziji pojava proteinurije povezana je s bržom progresijom bolesti. Neki autori su predložili da bi DD genotip angiotenzin I konvertaze mogao biti nepovoljan čimbenik prognoze u bubrežnih bolesti, ali i utjecati na učinke liječenja s ACE inhibitorima u bolesnika s proteinurijom. Rezultati dosadašnjih zapažanja o povezanosti polimorfizma ACE gena i arterijske hipertenzije često su oprečne i nekonzistentne, vjerojatno i zbog etničkih i geografskih varijacije. Cilj ove studije bio je ispitati utjecaj I/D polimorfizma ACE gena na ishod liječenja bolesnika s proteinurijom i povišenim krvnim tlakom s ACE inhibitorom (ramiprilom). U studiju je uključeno 66 bolesnika s proteinurijom (izlučivanje proteina urinom više od 500 mg dnevno) i arterijskom hipertenzijom. Bolesnici su bili podijeljeni u tri grupe prema ACE-genotipu (17 DD, 35 ID, 14 II) te liječeni ramiprilom i prospektivno praćeni godinu dana. Različiti klinički parametri uključujući dob, indeks tjelesne mase (IM), 24-h proteinuriju, kreatinin u serumu, klirens kreatinina (Ccr), sistolički i dijastolički krvni tlak (SKT i DKT), srednji arterijski tlak, izmjereni su prije i nakon liječenja. Insercijsko/delecijski polimorfizam ACE gena unutar introna 16 određen je metodom PCR. Rezultati su pokazali da nije bilo značajne razlike među genotipovima u kliničkim parametrima kao što su spol, dob, kreatinin, Ccr, SKT, DKT, 24-satna proteinurija (p>0,05). Bolesnici s ID genotipom imali su niži ITM (p=0,031). ACE inhibicija značajano smanjuje proteinuriju u svim skupinama (p<0,05). Utvrđena je statistički značajna razlika u postotku smanjenja proteinurije među genotipovima (p=0,042); za DD genotip bio je statistički značajno veći nego u ID (79,2±28,9% vs. 49,2±64,8%, p=0,015). Reductions in systolic and diastolic blood pressure did not differ significantly among genotypes.There was significant negative correlation between systolic blood pressure and percentage reductions of proteinuria (rs=–0,382; p=0,002).Nađena je statistički značajna negativna korelacija između sistoličkog krvnog tlaka i postotka smanjenja proteinurije (rs=– 0,382, p=0,002). Nismo uspjeli pronaći značajne razlike u ishodima liječenja s ACE inhibitorom između muškaraca i žena s obzirom na I/D polimorfizam ACE gena. D alel mogao bi biti koristan genski biljeg sa važnim kliničkim, terapeutskim i prognostičkim implikacijama u prepoznavanju bolesnika s proteinurijom koji imaju veći rizik za bubrežno oštećenje.

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