ENPP1 Q121 variant, increased pulse pressure and reduced insulin signaling, and nitric oxide synthase activity in endothelial cells.
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.
Bacci
Simonetta
S
Endocrine Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, San Giovanni Rotondo, Italy. dnnwba@tin.it
Di Paola
Rosa
R
Menzaghi
Claudia
C
Di Fulvio
Patrizia
P
Di Silvestre
Sara
S
Pellegrini
Fabio
F
Baratta
Roberto
R
Marucci
Antonella
A
Mastroianno
Sandra
S
Fini
Grazia
G
Formoso
Gloria
G
Consoli
Agostino
A
Perticone
Francesco
F
Frittitta
Lucia
L
Pandolfi
Assunta
A
Trischitta
Vincenzo
V
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
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