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Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE

Elisabetta Valoti1, Marina Noris1, Annalisa Perna1

  • 1Aldo e Cele Daccò Clinical Research Center for Rare Diseases, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Ranica, Italy.

Frontiers in Genetics
|August 21, 2019
PubMed

Insights

Genetic variants in complement factor H (CFH) are linked to increased risk of kidney and cardiovascular events in type 2 diabetes patients. These CFH variants may reduce the effectiveness of angiotensin-converting enzyme inhibitor (ACEi) therapy.

Area of Science:

  • Nephrology
  • Cardiology
  • Genetics

Background:

  • Complement activation plays a role in type 2 diabetes pathogenesis and complications.
  • Complement factor H (CFH) genetic variants are linked to organ damage via inefficient complement modulation.
  • The impact of specific CFH variants on renal and cardiovascular events in type 2 diabetes, and their interaction with ACEi therapy, remains unclear.

Purpose of the Study:

  • To investigate the association of the c.2808G>T (p.Glu936Asp) CFH polymorphism with renal and cardiovascular events in type 2 diabetes patients.
  • To determine if this CFH polymorphism influences the response to angiotensin-converting enzyme inhibitor (ACEi) therapy.
  • To analyze the risk stratification provided by the p.Glu936Asp polymorphism in the context of microalbuminuria and cardiovascular complications.

Main Methods:

  • Analysis of the p.Glu936Asp CFH polymorphism in 1,158 type 2 diabetes patients from the BENEDICT trial.
  • Prospective follow-up to assess new onset microalbuminuria and cardiovascular events.
  • Multivariable Cox regression analysis to evaluate the association between the polymorphism, ACEi therapy, and clinical outcomes.

Main Results:

  • The Asp/Asp genotype of the p.Glu936Asp CFH polymorphism was associated with a significantly increased risk of microalbuminuria (HR 3.25) and cardiovascular events (HR 2.68).
  • A significant interaction was observed between the p.Glu936Asp genotype and ACEi therapy regarding microalbuminuria prediction.
  • ACEi therapy was not nephroprotective in Asp/Asp homozygotes but was effective in Glu/Asp or Glu/Glu patients. Cardiovascular event risk was higher in ACEi-treated Asp/Asp homozygotes.

Conclusions:

  • Type 2 diabetes patients with the Asp/Asp genotype of the p.Glu936Asp CFH polymorphism face a higher risk of microalbuminuria and cardiovascular complications.
  • These patients may exhibit a diminished benefit from ACEi therapy.
  • Further research is warranted to validate these findings and explore potential therapeutic strategies for this patient subgroup.

Keywords:
ACE inhibitorscardiovascular riskcomplementdiabetesdiabetes complicationsfactor Hmicroalbuminuria

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