title: Synergism between asymmetric dimethylarginine (ADMA) and a genetic marker of uric acid in CKD progression.
abstract: OBJECTIVE
  We have recently reported that a polymorphism (rs734553) in a major urate transporter gene (GLUT9) is a strong predictor of incident renal events in stage 2-5 CKD patients implying that life-time exposure to high uric acid levels may be causally implicated in CKD progression. Since disturbed NO bioavailability is a major pathway whereby high uric may cause renal damage, we tested the interaction between the major endogenous inhibitor of NO synthase, asymmetric-dimethylargine (ADMA), and the rs734553 polymorphism for CKD progression in the same cohort.
  
  
  RESULTS
  Over a 29 ± 11 months follow-up the risk for incident renal events was higher in patients harboring the risk allele of the polymorphism (T) as compared to those without the risk allele (HR: 2.35, 95% CI: 1.25-4.42, P = 0.008) (p = 0.01). Similarly, patients with ADMA > median value had an increased risk for the same outcome (HR: 1.37, 95% CI: 1.06-1.76, P = 0.016). Interaction analysis showed a strong amplification by ADMA of the risk for renal events associated to the T allele because in adjusted (P = 0.016) and bootstrapping validated (P = 0.020) analyses the risk excess associated to this allele was progressively higher across increasing ADMA levels.
  
  
  CONCLUSIONS
  The rs734553 polymorphism, the strongest genetic marker of uric acid levels discovered so far, interacts with ADMA in determining the risk for CKD progression in CKD patients. This synergic interaction conforms to biological knowledge indicating that disturbed NO bio-availability is a critical pathway whereby life time exposure to high uric acid may engender renal damage.
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Testa
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Mallamaci
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Leonardis
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Spoto
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pisano
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguedolce
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tripepi
authors.affiliation: CNR-IFC/IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy. Electronic address: carmine.zoccali@tin.it.
authors.forename: C
authors.initials: C
authors.lastname: Zoccali
mesh_terms: D000368:Aged; D000483:Alleles; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002118:Calcium / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D023381:Endpoint Determination; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000235:genetics*; D012709:Serum Albumin / Q000378:metabolism; D014527:Uric Acid / Q000097:blood*
chemical_list: D005819:Genetic Markers; D051246:Glucose Transport Proteins, Facilitative; D006454:Hemoglobins; C411811:SLC2A9 protein, human; D012709:Serum Albumin; D014527:Uric Acid; C018524:N,N-dimethylarginine; D002097:C-Reactive Protein; D001120:Arginine; D003404:Creatinine; D019001:Nitric Oxide Synthase; D002118:Calcium
keywords: ADMA; CKD progression; Epidemiology; Polymorphism; Uric acid