Genetic Determinants of High-density Lipoprotein Cholesterol Efflux Capacity: Insights from Paraoxonase 1 Polymorphisms

Ryuji Toh

doi:10.5551/jat.ED267

See article vol. 31: 1263-1276

In recent years, it has been recognized that the quality, not just the quantity, of high-density lipoprotein (HDL) is important. Numerous studies have shown that the cholesterol efflux capacity (CEC) of HDL is a negative risk factor for cardiovascular disease independent of HDL cholesterol (HDL-C) levels^{1, 2)}. Under conditions such as insulin resistance, oxidative stress, and chronic inflammation, changes in the composition of HDL components and post-translational modifications of constituent proteins can impair HDL’s anti-atherosclerotic effects³⁾.

However, according to a large-scale family-based population study, CEC is estimated to be 13% heritable and independent of HDL-C⁴⁾. A genome-wide association study (GWAS) conducted on 5,293 French-Canadian individuals identified significant genetic signals associated with CEC in 5 loci related to lipid biology, including CETP, LIPC, LPL, APOA1/C3/A4/A5, and APOE/C1/C2/C4, as well as near PPP1CB/PLB1 and RBFOX3/ENPP7. After adjusting for HDL-C and triglyceride levels, the remaining significant association was observed with genetic variants at the APOE/C1/C2/C4 locus⁵⁾. In a GWAS involving 607 patients with coronary artery disease, the CDKAL1 locus was independently associated with CEC, distinct from HDL-C⁶⁾. In addition, a GWAS of 4,981 patients with chronic kidney disease revealed associations between CEC and KLKB1 and CLSTN2 genes⁷⁾. In contrast, endothelial lipase (EL), which preferentially hydrolyzes phospholipids in HDL, is encoded by the LIPG gene, and loss-of-function mutations in the LIPG gene have been shown to improve CEC alongside elevated HDL-C levels⁸⁾. However, recent reports have identified pathogenic LIPG variants that impair the HDL function^{9, 10)}.

Paraoxonase 1 (PON1) is a calcium-dependent enzyme with various enzymatic activities, including paraoxonase (POXase: hydrolysis of paraoxon), arylesterase (AREase: hydrolysis of aromatic esters), and diazoxonase activities¹¹⁾, and is mostly carried on HDL¹²⁾. PON1 plays an important role in inhibiting the production of peroxidized lipids and suppressing HDL oxidation. However, in patients with diabetes or coronary artery disease, decreased PON1 activity has been associated with a reduced CEC^13-15). In contrast, cardiac rehabilitation and statins have been shown to improve both the PON1 activity and CEC^{16, 17)}. Genetic polymorphisms of PON1 influence its enzyme activity, and the polymorphism at amino acid position 192, whether glutamine (Q) or arginine (R) (Q192R genotype), strongly affects POXase¹⁸⁾. However, the relationship between PON1 polymorphism and the CEC remains unclear.

In the present issue of JAT, Oniki et al. revealed that CEC was lower in the PON1 Q192R R/R genotype than in the Q/Q and Q/R genotypes¹⁹⁾. They found that PON1 Q192R R/R genotype carriers had higher POXase activity than Q/Q or Q/R carriers, but there was no overall correlation between CEC and POXase activity. In contrast, while there were no relationships between PON1 Q192R genotypes and AREase activity, the overall AREase activity was correlated with CEC¹⁹⁾.

Thus, although an association has been observed between the PON1 Q192R genotype and CEC, differences in POXase activity alone do not explain this relationship. Studies in healthy Japanese individuals have reported that the R allele has a higher POXase activity but a lower diazoxonase activity than the Q allele^{20, 21)}. However, the current study did not explore the relationship between diazoxonase activity and CEC. In addition, the substrates used for measuring POXase, AREase, and diazoxonase enzymatic activities are not naturally present in the body, suggesting that lactonase activity (hydrolysis of lactones) may represent the physiological function of PON1 ²²⁾. Furthermore, it has been reported that cysteine at position 283 in the amino acid sequence is important for the antioxidant activity of PON1 ²³⁾. However, taken together, these differences in esterase activity may still not fully explain the relationship between the PON1 Q192R genotype and CEC.

The authors have suggested that the amino acid sequence at position 192 influences POXase activity and is also close to the presumed site where PON1 binds to HDL, which may affect the binding strength between PON1 and HDL, influencing CEC¹⁹⁾. In addition, the weaker antioxidant activity of the PON1 Q192R R allele than that of the Q allele may result in inadequate suppression of LDL oxidation, potentially leading to HDL oxidation via oxidized LDL and thereby a reduced CEC¹⁹⁾.

Further investigations are needed to address 1) whether or not PON1 polymorphisms truly impact the CEC, 2) the mechanisms through which PON1 polymorphisms affect the CEC, and 3) the impact of PON1 polymorphisms on the CEC in the pathophysiology of atherosclerotic cardiovascular diseases.

Disclosures

Ryuji Toh belongs to an endowed chair with funding from Sysmex Corporation.

References

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