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
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=3.2×10-18) in a third study (n=957) and with an increased number of HDL particles of smaller size (P=3.4×10-17) 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=1.2×10-3; odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P=1.0×10-3). 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.
|Keywords||HDL, PLTP protein, adult, aged, article, atherosclerosis, atorvastatin, cardiovascular disease, cardiovascular risk, case control study, clinical trial, controlled clinical trial, controlled study, disease marker, disease predisposition, double blind, drug dose comparison, female, gene frequency, gene locus, genetic association, genetic identification, genetic transcription, genetic variability, genetics, genotype, high density lipoprotein, human, lipoproteins, major clinical study, male, non insulin dependent diabetes mellitus, particle size, phospholipid transfer protein, priority journal, procedure, randomized controlled trial, single nucleotide polymorphism|
|Persistent URL||dx.doi.org/10.1161/CIRCULATIONAHA.109.912519, hdl.handle.net/1765/21035|
Vergeer, M, Boekholdt, S.M, Sandhu, M.S, Ricketts, S.L, Wareham, N.J, Brown, M.J, … Dallinga-Thie, G.M. (2010). 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. Circulation (Baltimore), 122(5), 470–477. doi:10.1161/CIRCULATIONAHA.109.912519