Full Title: Paraoxonase 1 (PON1) genotype associated with heart rate variability in workers
Wei-Te Wua, Chao-Ching Wanga, Yu-Teh Chunga, Hui-Yi Liaoa, Ming-Hsiu Linb,
Yu-Fang Huanga, Trong-Neng Wua, c, Wan-Fen Lia, d*, Saou-Hsing Lioua, e, f*
a Division of Environmental Health and Occupational Medicine, National Health
Research Institutes, Miaoli, Taiwan.
b Institute of Occupational Safety and Health, Council of Labor Affairs, Executive
Yuan R.O.C
c Graduate Institute of Biostatistics, China Medical University, Taichung, Taiwan
d Division of Medical Genetics, Department of Medicine, University of Washington,
Seattle, USA
e Department of Public Health, National Defense Medical Center, Taipei, Taiwan
f Institute of Environmental Health, College of Public Health, China Medical
Correspondence:
Wan-Fen Li and Saou-Hsing Liou,
Division of Environmental Health & Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County, 35053, Taiwan, ROC.
Tel: 886-37-246166, ext. 36500 Fax: 886-37-584-075
E-mail: [email protected]
The epidemiologic studies mentioned that low serum Paraoxonase 1 (PON1) activity levels and human PON1 gene were both associated with increased risk of cardiovascular disease . Animal studies have reported that PON1-deficient mice had increased oxidative stress in both serum and macrophages and were more susceptible to developing atherosclerosis when fed on a high-fat diet . Moreover, antioxidant enzyme PON1 could be an important determinant of the capacity of HDL to stimulate endothelial nitric oxide (NO) production and to exert endothelial atheroprotective effects . The concept supported that HDL-associated PON1 activity impacts on the effects of HDL on endothelial NO production. However, it is still unknown that whether antioxidant enzyme PON1 changes vascular endothelial dysfunction to induce an alteration in vascular autonomic control. The purpose of the study was to exam whether PON1 genotype or NPs exposure has an association with HRV levels.
We recruited 235 workers exposed to NM and 185 non-exposed controls from 14 NM handling plants in Taiwan from 2009 to 2011. All subjects had no personal history of heart disease. For each participant, we collected blood specimens to determine the genotype of the PON1 Q192R polymorphism and PON1 paraoxonase and arylesterase activities. In addition, the subject also underwent an Autonomic Nerve Function (ANS) (SA-3000P; Medicore, Seoul, South Korea) Test during their routine health check-up in the mornings. The subjects complied with of HRV
guidelines that restricted talking, eating, drinking, any physical or mental activity including sleeping, and sitting positions during the test period .
The status of an individual is accomplished through the use of a 2-substrate enzyme assay, utilizing paraoxonase and arylesterase activities (Figure 1). This plot clearly separates individuals into the 3 phenotypes of PON1192 activity (low-level, intermediate-level, and high-level PON1 activities). In multivariate regression model 1 and model 2, after controlling for the subjects age, years on the job, BMI, gender, and cigarette smoking, RR homozygosity was a significant determinant for
LnRMSSD, and LnHF compared to QR and RR genotypes. Similar associations between PON1 paraoxonase/ arylesterase activities and HRV RMSSD(Ln , Ln HF,
LnPSI, and LnTP ) were observed in model 3 (Table 1).
Cardiac autonomic modulation is the main regulator of HRV, which is
considered an indirect indicator for the physiological response of ANS, reflecting a combined sympathetic and parasympathetic activity. Decrease in HRV could be a response to inflammation caused by systemic oxidative stress and could be a risk factor for cardiovascular morbidity and mortality in healthy as well as those individuals with existing cardiovascular disease . Previous studies have shown that individuals who are either RR homozygotes or have a high paraoxonase activity had lower levels of systemic oxidative stress and were at reduced risk for major
cardiovascular events . Antioxidant enzyme PON1 has also been an important determinant of the capacity of HDL to stimulate endothelial nitric oxide (NO) production and to exert endothelial atheroprotective effects . Thus the plausible explanation is that the protective effect of PON1 on HRV may be a result of an overall decrease in systemic oxidative stress and likely to change in vascular
autonomic control or vascular endothelial dysfunction by the affected bioavailability of NO.
In summary, this study found an association of PON1 Q192R genotype and PON1 activities with HRV. Subjects who are RR homozygotes or have high PON1 activities were found to have elevated HRV, a marker indicating good cardiac autonomic modulation. These results imply that PON1 Q192R genotype may be protecting the cardiovascular system. However, further evaluation with a larger population are requested to validate this association.
Acknowledgments
This study was partly supported by National Health Research Institutes (98A1-EOSP03-014, 99A1-(98A1-EOSP03-014, 00A1-(98A1-EOSP03-014, 01A1-EOSP03-014) and Institute of Occupational Safety and Health (IOSH98-M323, IOSH99-M323, IOSH100-M323, IOSH101-M323), Taiwan, ROC. The authors thank all the study
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