Abstract
Paraoxonase 1 (PON1) is a serum enzyme associated with high density lipoprotein (HDL) regulation through its paraoxonase and arylesterase activity. PON1 inhibits the oxidation of HDL and low density lipoprotein (LDL), and is involved in the pathogenesis of a variety of diseases including atherosclerosis. Conversely, mutations in the low density lipoprotein receptor (LDLR) result in failure of receptor mediated endocytosis of LDL leading to its elevated plasma levels and onset of familial hypercholesterolemia (FH). In the current study we investigated the role of PON1 polymorphisms rs662; c.575A > G (p.Gln192Arg) and rs854560; c.163T > A (p.Leu55Met) in a large family having FH patients harboring a functional mutation in LDLR. Genotypes were revealed by RFLP, followed by confirmation through Sanger sequencing. PON1 activity was measure by spectrophotometry. Our results show significantly reduced serum paraoxonase and arylesterase activities in FH patients compared with the healthy individuals of the family (p < 0.05). PON1 QQ192 genotype showed a significantly higher association with FH (p=0.0002). PON1 Q192 isoform was associated with reduced serum paraoxonase activity by in silico analysis and PON1 R192 exhibited higher serum paraoxonase and arylesterase activity than the other polymorphs. Our results highlight that the combination of LDLR mutations and PON1 MMQQ genotypes may lead to severe cardiac events.
Highlights
The human paraoxonase (PON) gene family located on the long arm of chromosome 17 consists of three members, each of which coding for three different calcium dependent esterases: paraoxonase 1 (PON1), PON2, and PON3 (La Du et al, 1993; Li et al, 2003; Mackness and Mackness, 2015)
We report on the role of PON1 coding sequences of single nucleotide polymorphisms (SNPs) rs662 (c.575A > G; p.Gln192Arg) and rs854560 (c.163T > A (p.Leu55Met) in relation to resultant paraoxonase and arylesterase activity in hypercholesterolemia patients with mutated low density lipoprotein receptor (LDLR)
There was no significant difference between patients and healthy individuals with respect to mean ± SD values of age, gender and body mass index (BMI)
Summary
The human paraoxonase (PON) gene family located on the long arm of chromosome 17 consists of three members, each of which coding for three different calcium dependent esterases: PON1, PON2, and PON3 (La Du et al, 1993; Li et al, 2003; Mackness and Mackness, 2015). PON1 and PON3 are plasma HDL-associated enzymes with antioxidant activities, albeit with differences (Mackness et al, 1993). PON1 is associated with high density lipoprotein (HDL) in human serum and prevents oxidation of both low density lipoprotein (LDL) and HDL (Aviram et al, 1998; Durrington et al, 2001; Mackness et al, 1996). The inhibition of LDL and HDL oxidation may protect against various pathologies including cardiovascular diseases (CVD); PON1, is considered the gene of longevity (Lescai et al, 2009, Martinelli et al, 2013). A relationship between paraoxonase 1 (PON1) genotype status, antioxidant, and anti-atherogenic capacity of the enzyme has been suggested previously (Mackness et al, 1993, 2002; Rosenblat et al, 2006). PON1 arylesterase/paraoxonase activities have been shown to be inversely correlated to the risk of coronary heart diseases and hypercholesterolemia (Humbert et al, 1993; Garin et al, 1997; Bryk et al, 2005)
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