PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Abstract

Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline ( 1, 2 ). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women ( 2 ). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline ( 3 ).In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9 ), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels ( P = 0.0042), diabetes ( P = 7.28 × 10 ؊ 5 ), paraoxonase 1 (PON1) activity ( P = 0.019), statin use ( P = 0.026), PLTP SNP rs4810479 ( P = 6.38 × 10 ؊ 7 ), and PCIF1 SNP rs181914932 ( P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

“…There is no literature evidence for any potential link for ZNF335 to AAA and the only identified genetic association of ZNF335 is with celiac disease43. Although rs181914932 is upstream and more proximal to PCIF1, it has been associated with the activity of PLTP44, an adjacent gene in the same locus. Our eQTL analyses demonstrated an association between the lead SNP we assessed at this locus (rs3827066) and PLTP expression in aortic tissue (Online Tables XX and XXI).…”

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

“…Variant rs191487796, 20kb upstream of LIPC, has not been reported in the literature. Variant rs4810479, 4kb upstream of PLTP, in a putative enhancer region, has been previously shown to associate with mean HDL-C particle size and PLTP activity, which is inversely correlated with carotid artery disease (22,23). The APOA5 missense variant rs3135506, the only variant on haplotype APOA5*3, has a PolyPhen2 score of 0.99, indicating it is 'probably damaging'.…”

High-density lipoprotein characteristics and coronary heart disease: a Mendelian randomization study

“…The third HDL-related locus encodes the PDX1 C-Terminal Inhibiting Factor 1 and is located next to the PLTP gene, which expresses the phospholipid transfer protein, an enzyme involved in HDL remodeling/stabilization and the generation of lipid-free/lipidpoor small HDLs 29 . PCIF1-related gene variants have been shown to modulate phospholipid transfer protein function in other studies 36 . Fourth, TTC39B encodes the tetratricopeptide repeat domain protein 39B, whose genetic variants had already been associated with HDL-C levels and CAD in previous works 32,37 .…”