title: The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients.
abstract: OBJECTIVE
  Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals.
  
  
  METHODS
  A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.).
  
  
  RESULTS
  Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction).
  
  
  CONCLUSIONS
  The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding.
authors.affiliation: Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bacci
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizza
authors.forename: Sabrina
authors.initials: S
authors.lastname: Prudente
authors.forename: Belinda
authors.initials: B
authors.lastname: Spoto
authors.forename: Christine
authors.initials: C
authors.lastname: Powers
authors.forename: Antonio
authors.initials: A
authors.lastname: Facciorusso
authors.forename: Antonio
authors.initials: A
authors.lastname: Pacilli
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Testa
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Stolfo
authors.forename: Francesca
authors.initials: F
authors.lastname: Mallamaci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Davide
authors.initials: D
authors.lastname: Mangiacotti
authors.forename: Filippo
authors.initials: F
authors.lastname: Aucella
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
authors.forename: Ernest V
authors.initials: EV
authors.lastname: Gervino
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hauser
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Cosmo
authors.forename: Fabio
authors.initials: F
authors.lastname: Pellegrini
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D015994:Incidence; D007558:Italy; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics*; D012307:Risk Factors; D018709:Statistics, Nonparametric; D044465:White People / Q000235:genetics
chemical_list: D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases