title: ENPP1 Q121 variant, increased pulse pressure and reduced insulin signaling, and nitric oxide synthase activity in endothelial cells.
abstract: OBJECTIVE
  Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk.
  
  
  RESULTS
  We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP (P=8.0 x 10(-4)). In the families, the Q121 variant accounted for 0.08 of PP heritability (P=9.4 x 10(-4)). This association was formally replicated in a second sample of 475 individuals (P=2.6 x 10(-2)) but not in 2 smaller samples of 289 and 236 individuals (P=0.49 and 0.21, respectively). In the individual patients' data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant (P=1.2 x 10(-3)). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation (P=0.03), Ser(473)-Akt phosphorylation (P=0.03), and NO synthase activity (P=0.003).
  
  
  CONCLUSIONS
  Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers.
authors.affiliation: Endocrine Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, San Giovanni Rotondo, Italy. dnnwba@tin.it
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bacci
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Paola
authors.forename: Claudia
authors.initials: C
authors.lastname: Menzaghi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Di Fulvio
authors.forename: Sara
authors.initials: S
authors.lastname: Di Silvestre
authors.forename: Fabio
authors.initials: F
authors.lastname: Pellegrini
authors.forename: Roberto
authors.initials: R
authors.lastname: Baratta
authors.forename: Antonella
authors.initials: A
authors.lastname: Marucci
authors.forename: Sandra
authors.initials: S
authors.lastname: Mastroianno
authors.forename: Grazia
authors.initials: G
authors.lastname: Fini
authors.forename: Gloria
authors.initials: G
authors.lastname: Formoso
authors.forename: Agostino
authors.initials: A
authors.lastname: Consoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Perticone
authors.forename: Lucia
authors.initials: L
authors.lastname: Frittitta
authors.forename: Assunta
authors.initials: A
authors.lastname: Pandolfi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D000328:Adult; D001794:Blood Pressure; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000502:physiology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011755:Pyrophosphatases / Q000235:genetics*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013599:Systole; D044465:White People / Q000235:genetics
chemical_list: D007328:Insulin; D019001:Nitric Oxide Synthase; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases