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@proceedings{1068268,
author = {Bartáková, Vendula and Malúšková, Denisa and Kuricová, Katarína and Tanhäuserová, Veronika and Pácal, Lukáš and Bělobrádková, Jana and Mužík, Jan and Pavlík, Tomáš and Krusová, Darja and Kaňková, Kateřina},
booktitle = {48th Annual Meeting EASD 2012},
doi = {http://dx.doi.org/10.1007/s00125-012-2688-9},
keywords = {Diabetic nephropathy, pharmacogenetics, diabetes mellitus, renin-angiotensin-aldosterone system},
language = {eng},
title = {Progression of diabetic nephropathy and genetic variability in the renin-angiotensin-aldosterone system: evidence for pharmacogenetic effects?},
year = {2012}
}
TY - CONF
ID - 1068268
AU - Bartáková, Vendula - Malúšková, Denisa - Kuricová, Katarína - Tanhäuserová, Veronika - Pácal, Lukáš - Bělobrádková, Jana - Mužík, Jan - Pavlík, Tomáš - Krusová, Darja - Kaňková, Kateřina
PY - 2012
TI - Progression of diabetic nephropathy and genetic variability in the renin-angiotensin-aldosterone system: evidence for pharmacogenetic effects?
KW - Diabetic nephropathy, pharmacogenetics, diabetes mellitus, renin-angiotensin-aldosterone system
N2 - Background and aims: Pathological over-activation of renin-angiotensin-aldosterone system (RAAS) as the key pathogenic mechanism of diabetic nephropathy (DN). Pharmacological blockade of RAAS represents main renoprotective treatment of DN. Several single nucleotide polymorphisms (SNPs) were shown to influence interindividual variability in RAAS (e.g circulating levels of RAAS compounds and enzyme activities) and could hypothetically also modify therapeutic effect of RAAS blockers. We aimed to study contribution of genetic variability in RAAS to the progression of DN and other adverse outcomes of diabetes taking into account RAAS blocking treatment in a quantitative manner. Materials and methods: A total of 391 diabetic patients and variable stage of kidney disease were prospectively followed for a median of 39 (IQR 20-58) months. We considered following end-points: (1) progression of DN, (2) major cardiovascular event (MCVE, non fatal myocardial infarction or stroke) and (3) all-cause mortality. Selected SNPs were genotyped using PCR: angiotensin converting enzyme (I/D ACE), angiotensinogen (ATG M235T), angiotensin II type I receptor (ATR1 A1166C), aldosterone synthase (CYP11B2-344T/C), hydroxysteroid dehydrogenase (HSD11B1 83557insA, HSD11B2 G534A) and mineralocorticoid receptor (MR G3514C, MR A4582C). Subjects were receiving following antihypertensive treatment: (1) angiotensin converting enzyme inhibitors only (ACEi, 36%), (2) angiotensin II receptor blockers only (ARBs, 14%), (3) both ACEi and ARBs (23%) and (4) no antihypertensive treatment (27%). Cumulative dose during the follow-up was expressed as units of Captopril for ACEi and units of Losartan for ARBs. Results: We found significant differences in mortality between carriers of genotypes of CYP11B2 -344T/C and ATG M235T (log-rank test, P=0.05 and 0.037, respectively) in univariate time-to-event analysis. Using Cox regression model carriers of the combination of risk genotypes exhibited significant difference in mortality (HR 2.70 95% CI 1.34-5.43, p=0.005) without significant contribution of treatment parameters. Conclusion: We identified significant genetic contribution of genetic variability in the RAAS to all-cause mortality of diabetic patients however no evidence of pharmacogenetic effects. More thorough analysis are currently under way. Acknowledgement: The study was supported by the grant NT/13198 from the Ministry of Health of Czech Republic.
ER -
BARTÁKOVÁ, Vendula, Denisa MALÚŠKOVÁ, Katarína KURICOVÁ, Veronika TANHÄUSEROVÁ, Lukáš PÁCAL, Jana BĚLOBRÁDKOVÁ, Jan MUŽÍK, Tomáš PAVLÍK, Darja KRUSOVÁ a Kateřina KAŇKOVÁ. Progression of diabetic nephropathy and genetic variability in the renin-angiotensin-aldosterone system: evidence for pharmacogenetic effects? In \textit{48th Annual Meeting EASD 2012}. ISSN~0012-186X. doi:10.1007/s00125-012-2688-9. 2012.
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