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Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes

Complement activation has been increasingly implicated in the pathogenesis of type 2 diabetes and its chronic complications. It is unknown whether complement factor H (CFH) genetic variants, which have been previously associated with complement-mediated organ damage likely due to inefficient complem...

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Autores principales: Valoti, Elisabetta, Noris, Marina, Perna, Annalisa, Rurali, Erica, Gherardi, Giulia, Breno, Matteo, Parvanova Ilieva, Aneliya, Petrov Iliev, Ilian, Bossi, Antonio, Trevisan, Roberto, Dodesini, Alessandro Roberto, Ferrari, Silvia, Stucchi, Nadia, Benigni, Ariela, Remuzzi, Giuseppe, Ruggenenti, Piero
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689971/
https://www.ncbi.nlm.nih.gov/pubmed/31428128
http://dx.doi.org/10.3389/fgene.2019.00681
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author Valoti, Elisabetta
Noris, Marina
Perna, Annalisa
Rurali, Erica
Gherardi, Giulia
Breno, Matteo
Parvanova Ilieva, Aneliya
Petrov Iliev, Ilian
Bossi, Antonio
Trevisan, Roberto
Dodesini, Alessandro Roberto
Ferrari, Silvia
Stucchi, Nadia
Benigni, Ariela
Remuzzi, Giuseppe
Ruggenenti, Piero
author_facet Valoti, Elisabetta
Noris, Marina
Perna, Annalisa
Rurali, Erica
Gherardi, Giulia
Breno, Matteo
Parvanova Ilieva, Aneliya
Petrov Iliev, Ilian
Bossi, Antonio
Trevisan, Roberto
Dodesini, Alessandro Roberto
Ferrari, Silvia
Stucchi, Nadia
Benigni, Ariela
Remuzzi, Giuseppe
Ruggenenti, Piero
author_sort Valoti, Elisabetta
collection PubMed
description Complement activation has been increasingly implicated in the pathogenesis of type 2 diabetes and its chronic complications. It is unknown whether complement factor H (CFH) genetic variants, which have been previously associated with complement-mediated organ damage likely due to inefficient complement modulation, influence the risk of renal and cardiovascular events and response to therapy with angiotensin-converting enzyme inhibitors (ACEi) in type 2 diabetic patients. Here, we have analyzed the c.2808G>T, (p.Glu936Asp) CFH polymorphism, which tags the H3 CFH haplotype associated to low plasma factor H levels and predisposing to atypical hemolytic uremic syndrome, in 1,158 type 2 diabetics prospectively followed in the Bergamo nephrologic complications of type 2 diabetes randomized, controlled clinical trial (BENEDICT) that evaluated the effect of the ACEi trandolapril on new onset microalbuminuria. At multivariable Cox analysis, the p.Glu936Asp polymorphism (Asp/Asp homozygotes, recessive model) was associated with increased risk of microalbuminuria [adjusted hazard ratio (HR) 3.25 (95% CI 1.46–7.24), P = 0.0038] and cardiovascular events [adjusted HR 2.68 (95% CI 1.23–5.87), P = 0.013]. The p.Glu936Asp genotype significantly interacted with ACEi therapy in predicting microalbuminuria. ACEi therapy was not nephroprotective in Asp/Asp homozygotes [adjusted HR 1.54 (0.18–13.07), P = 0.691 vs. non-ACEi-treated Asp/Asp patients], whereas it significantly reduced microalbuminuria events in Glu/Asp or Glu/Glu patients [adjusted HR 0.38 (0.24–0.60), P < 0.0001 vs. non-ACEi-treated Glu/Asp or Glu/Glu patients]. Among ACEi-treated patients, the risk of developing cardiovascular events was higher in Asp/Asp homozygotes than in Glu/Asp or Glu/Glu patients [adjusted HR 3.26 (1.29–8.28), P = 0.013]. Our results indicate that type 2 diabetic patients Asp/Asp homozygotes in the p.Glu936Asp CFH polymorphism are at increased risk of microalbuminuria and cardiovascular complications and may be less likely to benefit from ACEi therapy. Further studies are required to confirm our findings.
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spelling pubmed-66899712019-08-19 Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes Valoti, Elisabetta Noris, Marina Perna, Annalisa Rurali, Erica Gherardi, Giulia Breno, Matteo Parvanova Ilieva, Aneliya Petrov Iliev, Ilian Bossi, Antonio Trevisan, Roberto Dodesini, Alessandro Roberto Ferrari, Silvia Stucchi, Nadia Benigni, Ariela Remuzzi, Giuseppe Ruggenenti, Piero Front Genet Genetics Complement activation has been increasingly implicated in the pathogenesis of type 2 diabetes and its chronic complications. It is unknown whether complement factor H (CFH) genetic variants, which have been previously associated with complement-mediated organ damage likely due to inefficient complement modulation, influence the risk of renal and cardiovascular events and response to therapy with angiotensin-converting enzyme inhibitors (ACEi) in type 2 diabetic patients. Here, we have analyzed the c.2808G>T, (p.Glu936Asp) CFH polymorphism, which tags the H3 CFH haplotype associated to low plasma factor H levels and predisposing to atypical hemolytic uremic syndrome, in 1,158 type 2 diabetics prospectively followed in the Bergamo nephrologic complications of type 2 diabetes randomized, controlled clinical trial (BENEDICT) that evaluated the effect of the ACEi trandolapril on new onset microalbuminuria. At multivariable Cox analysis, the p.Glu936Asp polymorphism (Asp/Asp homozygotes, recessive model) was associated with increased risk of microalbuminuria [adjusted hazard ratio (HR) 3.25 (95% CI 1.46–7.24), P = 0.0038] and cardiovascular events [adjusted HR 2.68 (95% CI 1.23–5.87), P = 0.013]. The p.Glu936Asp genotype significantly interacted with ACEi therapy in predicting microalbuminuria. ACEi therapy was not nephroprotective in Asp/Asp homozygotes [adjusted HR 1.54 (0.18–13.07), P = 0.691 vs. non-ACEi-treated Asp/Asp patients], whereas it significantly reduced microalbuminuria events in Glu/Asp or Glu/Glu patients [adjusted HR 0.38 (0.24–0.60), P < 0.0001 vs. non-ACEi-treated Glu/Asp or Glu/Glu patients]. Among ACEi-treated patients, the risk of developing cardiovascular events was higher in Asp/Asp homozygotes than in Glu/Asp or Glu/Glu patients [adjusted HR 3.26 (1.29–8.28), P = 0.013]. Our results indicate that type 2 diabetic patients Asp/Asp homozygotes in the p.Glu936Asp CFH polymorphism are at increased risk of microalbuminuria and cardiovascular complications and may be less likely to benefit from ACEi therapy. Further studies are required to confirm our findings. Frontiers Media S.A. 2019-07-26 /pmc/articles/PMC6689971/ /pubmed/31428128 http://dx.doi.org/10.3389/fgene.2019.00681 Text en Copyright © 2019 Valoti, Noris, Perna, Rurali, Gherardi, Breno, Parvanova Ilieva, Petrov Iliev, Bossi, Trevisan, Dodesini, Ferrari, Stucchi, Benigni, Remuzzi and Ruggenenti http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Valoti, Elisabetta
Noris, Marina
Perna, Annalisa
Rurali, Erica
Gherardi, Giulia
Breno, Matteo
Parvanova Ilieva, Aneliya
Petrov Iliev, Ilian
Bossi, Antonio
Trevisan, Roberto
Dodesini, Alessandro Roberto
Ferrari, Silvia
Stucchi, Nadia
Benigni, Ariela
Remuzzi, Giuseppe
Ruggenenti, Piero
Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes
title Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes
title_full Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes
title_fullStr Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes
title_full_unstemmed Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes
title_short Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes
title_sort impact of a complement factor h gene variant on renal dysfunction, cardiovascular events, and response to ace inhibitor therapy in type 2 diabetes
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689971/
https://www.ncbi.nlm.nih.gov/pubmed/31428128
http://dx.doi.org/10.3389/fgene.2019.00681
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