Published online before print August 13, 2009, doi: 10.1161/ATVBAHA.109.189191
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© 2009 American Heart Association, Inc.
Clinical and Population Studies |
ENPP1 Q121 Variant, Increased Pulse Pressure and Reduced Insulin Signaling, and Nitric Oxide Synthase Activity in Endothelial Cells
From the Endocrine Unit (S.B., S.M.), the Research Unit of Diabetes and Endocrine Diseases (R.D.P., C.M., A.M., G. Fini, V.T.), and the Unit of Biostatistics (F.P.), IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy; the Departments of Medicine and Aging Sciences (P.D.F., G. Formoso, A.C.) and Biomedical Sciences (S.D.S., A.P.), University "G. d’Annunzio," Aging Research Center, Ce.S.I., "G. d’Annunzio" University Foundation, Chieti-Pescara, Italy; the Department of Clinical Pharmacology and Epidemiology (F. Pellegrini), "Consorzio Mario Negri Sud," S. Maria Imbaro, Chieti, Italy; the Endocrine Unit, Department of Internal and Specialistic Medicine (R.B., L.F.), University of Catania Medical School, Garibaldi Hospital, Catania, Italy; the Department of Experimental and Clinical Medicine "G. Salvatore" (F. Perticone), University Magna Graecia of Catanzaro, Catanzaro, Italy; the Department of Medical Pathophysiology (V.T.), "Sapienza" University, Rome, Italy; and IRCCS "Casa Sollievo della Sofferenza-Mendel Institute" (V.T.), Rome, Italy.
Correspondence to Simonetta Bacci, MD, Endocrine Unit, IRCCS "Casa Sollievo della Sofferenza," Viale Cappuccini 1, San Giovanni Rotondo (FG), Italy. E-mail dnnwba{at}tin.it or Vincenzo Trischitta, MD, Research Unit of Diabetes and Endocrine Diseases, IRCCS "Casa Sollievo della Sofferenza," Viale Cappucini 1, San Giovanni Rotondo (FG), Italy. Email: vicenzo.trischitta@uniromal.it.
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.
Methods and 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=8.0x10–4). In the families, the Q121 variant accounted for 0.08 of PP heritability (P=9.4x10–4). This association was formally replicated in a second sample of 475 individuals (P=2.6x10–2) 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=1.2x10–3). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation (P=0.03), Ser473-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.
The ENPP1 K121Q polymorphism has been associated with insulin resistance and atherosclerosis. Here the Q121 variant is associated with increased PP (P=1.2x10–3 in 1985 individuals) and reduced insulin signaling (P<0.05) and NO production (P<0.01) in human endothelial cells, thus suggesting it has a role on vascular biology and cardiovascular risk.
Key Words: ENPP-1 gene • cardiovascular disease • arterial stiffness • endothelial dysfunction • insulin resistance