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La proteina di trasferimento dei fosfolipidi favorisce l'aterosclerosi?

La proteina di trasferimento dei fosfolipidi (PLTP) ha un ruolo chiave nel favorire il trasporto dei fosfolipidi dalle VLDL alle HDL e contribuisce pertanto al rimodellamento delle HDL. Dato che la PLTP è positivamente correlata con la concentrazione plasmatica delle HDL e dell'apo A-I, si è pensato che essa avesse un ruolo ateroprotettivo. In realtà, alti livelli plasmatici di PLTP sono stati trovati associati ad un rischio maggiore di malattia coronarica. A conferma del possibile ruolo pro-aterogeno della PLTP, Vergeer e Coll. riportano varianti genetiche del locus che codifica per la PLTP che si riflettono in una più bassa attività della proteina, una più alta concentrazione di HDL di piccole dimensioni ed un ridotto rischio di malattia coronarica.

Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility.

Vergeer M, Boekholdt SM, Sandhu MS, Ricketts SL, Wareham NJ, Brown MJ, de Faire U, Leander K, Gigante B, Kavousi M, Hofman A, Uitterlinden AG, van Duijn CM, Witteman JC, Jukema JW, Schadt EE, van der Schoot E, Kastelein JJ, Khaw KT, Dullaart RP, van Tol A, Trip MD, Dallinga-Thie GM.

Circulation 2010;122:470-77

BACKGROUND: In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk.
METHODS AND RESULTS: We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined n=384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (P=3.2x10(-18)) in a third study (n=957) and with an increased number of HDL particles of smaller size (P=3.4x10(-17)) in a fourth study (n=3375). In a combination of 5 cardiovascular disease case-control studies (n=4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; P=1.2x10(-3); odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P=1.0x10(-3)).
CONCLUSIONS: A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit.

Circulation 2010;122:470-77