Sex difference: an important issue to consider in epidemiological and clinical studies dealing with serum paraoxonase-1

Abstract

The aim of this study was to evaluate the influence of sex on serum paraoxonase 1 (PON1) activities and on its relationship with cardiovascular disease risk factors such as overall and central obesity. Arylesterase and lactonase activities of PON1 were assessed in 374 women and 92 men. Both arylesterase and lacto nase activities were significantly higher in women compared to men (p<0.001), irrespectively of confounders such as high density lipoprotein cholesterol, age, smoking and body mass index or waist circumference. Sex also strongly influenced the interplay between PON1 and both fat measures, with only the arylesterase showing a significant and independent inverse correlation with the former parameter (r = −0.248, p<0.001) and the risk of overall obesity (odds ratio: 0.559, 95% confidence interval: 0.340-0.919) in women, but not in men; conversely, neither of the two activities remained associated with waist circumference in men or women after full adjustment. Noteworthy, the association between arylesterase and BMI in the female subsample was significant among women younger than forty five years (r = −0.453, p<0.001, R 2 = 0.207). In conclusion, our study suggests that sex might chiefly influence PON1 activity and its contribution to cardiovascular disease risk. Further studies are needed to confirm and clarify our preliminary findings.

Sex Difference Impacts on the Relationship between Paraoxonase-1 (PON1) and Type 2 Diabetes

“…This would suggest that T2D attenuates the reported “double” physiological female sex advantage represented by the high HDL-c concentration and PON1 activity level [ 1 , 47 , 48 ]. As previously postulated by us and others, high levels of this enzyme might contribute to the lower risk of CVD in women compared to men [ 23 , 24 , 49 ]. Thus, the sex-dependent decrease in PON1 could be one of many biological factors explaining why T2D increases the risk for CVD in females to a greater extent than in males (see comprehensive review on sex difference in T2D complications and comorbidities [ 1 , 2 , 3 ]).…”

“…Lipoprotein oxidation is central to the development of macro- (atherosclerosis) and micro-vascular disease in diabetes, as highlighted by the toxicity of oxidized lipoproteins for endothelial cells and pericytes in retinal capillaries [ 21 , 22 ]. Some studies report that PON1 activity is greater in women than men, this could be ascribed to an influential effect of sex hormones on the expression of the protein [ 23 , 24 ]. Indeed, in vivo studies found that mice treated with a male-pattern growth hormone had decreased hepatic mRNA levels of PON1 [ 25 ], whereas estrogens increased the stabilization/regulation of PON1 without affecting its expression [ 26 ].…”

“…Recently, we have shown that sex significantly affects the interplay of PON1 with CVD risk factors, such as overall and central obesity [ 23 ]. In this study, we investigated in a large population of men and women whether the effect of gender on PON1 might contribute to the sexual dimorphism that characterizes complicated T2D.…”

A Multi-Omics Analysis of PON1 Lactonase Activity in Relation to Human Health and Disease

“…A more recent article also focused on the influence of gender on PON1, with TBL as a substrate, and concludes that gender does influence lactonase activity (Trentini et al, 2019 ). Trentini et al detected higher PON1 lactonase activity among women than among men, even after accounting for confounders such as concentrations of HDL and cholesterol, age, smoking, body mass index, and waist circumference.…”

“…Trentini et al detected higher PON1 lactonase activity among women than among men, even after accounting for confounders such as concentrations of HDL and cholesterol, age, smoking, body mass index, and waist circumference. The authors reported a significant difference between genders for both lactonase and arylesterase activities (Trentini et al, 2019 ).…”