title: Apolipoprotein E polymorphism modulation of asymmetric dimethylarginine in hypertensive patients is determined by renal function.
abstract: BACKGROUND
  Endothelial dysfunction is considered an early step of atherosclerotic vascular disease. Asymmetric dimethylarginine (ADMA), the main endogenous inhibitor of nitric oxide synthase (NOS), plays a critical role in the process of atherosclerosis in a uremic environment. Increased plasma ADMA not only works as a cardiovascular morbidity biomarker but it is also involved in the genesis of atherosclerosis in renal disease. Considering the relationships of apolipoprotein E(ApoE) polymorphism with LDL cholesterol (LDL-C) levels and coronary risk, it is possible that it brings on susceptibility to endothelial dysfunction and atherogenesis seen on uremia.
  
  
  METHODS
  Six hundred twenty patients were stratified according to glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) formula: group I > 60 mL/min, group II ≤ 60 mL/min and > 15 mL/min, and group III ≤ 15 mL/min or in hemodialysis. Polymorphic ApoE analysis was performed by polymerase chain reaction amplification (PCR). Plasma ADMA levels were measured by high performance liquid chromatography (HPLC). Groups were compared on clinical and laboratory characteristics as well as allele and genotype distribution towards.
  
  
  RESULTS
  The ε2 allele of ApoE was present in 62 (10.3 %) patients, ε3 allele in 581 (96.2 %), and ε4 allele in 114 (18.9 %). Their distribution among the 3 groups was uniform. Such uniformity was not observed when we considered endothelial function measured by asymmetric dimethylarginine. In group III, the frequency of ε4 allele was significantly lower in the third tertile compared with the first tertile (14.7 versus 53.3 %, P = 0.000; Pearson chi-square). In groups I and II, there was no difference in allele frequency according to ADMA levels. This association remained significant even after confouding factors corrections (OR 0.329, 95 % CI 0.155 - 0.699, P = 0.004).
  
  
  CONCLUSIONS
  The results of this study shows that the frequency of ε4 allele of ApoE is significantly lower among hypertensive patients on hemodialysis with the highest levels of ADMA. Uremia is capable of determining lower plasma ADMA levels in hypertensive ε4 allele carriers.
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. msmarrocos@gmail.com.
authors.forename: Mauro Sergio Martins
authors.initials: MS
authors.lastname: Marrocos
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. andreialkmin@uol.com.br.
authors.forename: Andrei Alkmin
authors.initials: AA
authors.lastname: Teixeira
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. marie.quinto@unifesp.br.
authors.forename: Beata Marie
authors.initials: BM
authors.lastname: Quinto
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. melosilmara@ymail.com.
authors.forename: Silmara de Melo
authors.initials: Sde M
authors.lastname: Carmona
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. mari.kuni@gmail.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Kuniyoshi
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. cjorodrigues@uol.com.br.
authors.forename: Cassio Jose
authors.initials: CJ
authors.lastname: Rodrigues
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. dalboni@unifesp.br.
authors.forename: Maria Aparecida
authors.initials: MA
authors.lastname: Dalboni
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. silvia.hemod@hrim.com.br.
authors.forename: Silvia
authors.initials: S
authors.lastname: Manfredi
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. dialisefor@yahoo.com.br.
authors.forename: Maria Eugênia
authors.initials: ME
authors.lastname: Canziani
authors.affiliation: Nephrology Division, Universidade Federal de São Paulo, R. Pedro de Toledo, 781 14 .andar, Vila Clementino, São Paulo, CEP, 04039-032, Brazil. marcelocbatista@uol.com.br.|Nephrology Division-New England Medical Center, Tufts University, Boston, MA, USA. marcelocbatista@uol.com.br.|Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil. marcelocbatista@uol.com.br.
authors.forename: Marcelo Costa
authors.initials: MC
authors.lastname: Batista
mesh_terms: D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D003710:Demography; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D007677:Kidney Function Tests; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044469:Racial Groups / Q000235:genetics; D017582:Renal Replacement Therapy
chemical_list: D001057:Apolipoproteins E; C018524:N,N-dimethylarginine; D001120:Arginine