title: A polymorphism in a major antioxidant gene (Kelch-like ECH-associated protein 1) predicts incident cardiovascular events in chronic kidney disease patients: an exploratory study.
abstract: OBJECTIVE
  Oxidative stress is considered a major pathway conducive to cardiovascular disease in chronic kidney disease (CKD) patients. However, observational studies and clinical trials testing this relationship are controversial. The Nuclear factor-erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) system is a major system regulating antioxidant mechanisms in living organisms. Owing to the fact that genes are transmitted randomly (Mendelian randomization), genetic variants may provide unconfounded assessment of putative causal risk factors.
  
  
  METHODS
  We have therefore explored the association of eight polymorphisms in the Nrf2 gene and three polymorphisms in the Keap1 gene (capturing over 80% of the genetic variance in the same genes) with cardiovascular events in a multicenter cohort study of 758 CKD patients.
  
  
  RESULTS
  During the follow-up period, 117 patients had fatal and nonfatal cardiovascular events and 42 died. The hazard rate of fatal and nonfatal cardiovascular outcomes was about twice higher in patients with the AA or the CA genotype (dominant model) in the rs110857735 polymorphism of the Keap1 gene (hazard rate: 1.85, 95% CI: 1.20-2.84, P = 0.005) than in those with the CC genotype. Further analyses adjusting for Framingham risk factors and CKD-specific risk factors and a bootstrapping validation analysis did not modify the strength of this association. No association was registered between other Keap1 and Nrf2 polymorphisms and cardiovascular disease in the same cohort.
  
  
  CONCLUSIONS
  In this exploratory study a gene-variant in Keap1, a major gene regulating the antioxidant response, predicts incident cardiovascular events in CKD patients. This finding is in keeping with the hypothesis implicating oxidative stress in cardiovascular disease in this population.
authors.affiliation: aCNR-IFC, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension bNephrology, Dialysis and Transplantation Unit, Reggio Calabria, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Testa
authors.forename: Daniela
authors.initials: D
authors.lastname: Leonardis
authors.forename: Belinda
authors.initials: B
authors.lastname: Spoto
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Sanguedolce
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Parlongo
authors.forename: Anna
authors.initials: A
authors.lastname: Pisano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.forename: Francesca
authors.initials: F
authors.lastname: Mallamaci
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
mesh_terms: D002318:Cardiovascular Diseases / Q000150:complications / Q000453:epidemiology* / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000032:analysis*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000235:genetics*; D012307:Risk Factors
chemical_list: C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human