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Interaction effects between Paraoxonase 1 variants and cigarette smoking on risk of coronary heart disease in a Singaporean Chinese population

  • Yi Han
    Affiliations
    Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore
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  • Rajkumar Dorajoo
    Affiliations
    Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
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  • Tingjing Ke
    Affiliations
    Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore
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  • Burger Ayala
    Affiliations
    Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore

    School of Public Health and Community Medicine, Hebrew University of Jerusalem, Israel
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  • Xuling Chang
    Affiliations
    Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore
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  • Chiea-Chuen Khor
    Affiliations
    Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
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  • Rob M. van Dam
    Affiliations
    Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
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  • Jian-Min Yuan
    Affiliations
    Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
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  • Woon-Puay Koh
    Affiliations
    Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore

    Duke-NUS Graduate Medical School Singapore, Singapore
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  • Jianjun Liu
    Affiliations
    Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore

    Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
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  • Daniel Y.T. Goh
    Affiliations
    Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore
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  • Yechiel Friedlander
    Correspondence
    Corresponding author. Unit of Epidemiology, Hebrew University-Hadassah Braun School of Public Health, POB 12272, Jerusalem 91120, Israel.
    Affiliations
    School of Public Health and Community Medicine, Hebrew University of Jerusalem, Israel
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  • Chew-Kiat Heng
    Correspondence
    Corresponding author. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 12, 1E Kent Ridge Road, Singapore 119228, Singapore.
    Affiliations
    Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Khoo Teck Puat – National University Children's Medical Institute, National University Health System, Singapore
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      Highlights

      • 2 PON1 genetic variants–smoking interactions impact coronary heart disease risk.
      • T allele of nonsynonymous rs662 variant is associated with higher risk in smokers.
      • Novel interaction of rs3735590 at miRNA binding site and smoking is identified.
      • CC homozygote of rs3735590 is associated with lower risk in never-smokers.

      Abstract

      Objective

      Paraoxonase 1 (PON1) plays an important role in reducing the risk of coronary heart disease (CHD). Smoking is known to reduce PON1 activity. We aimed to investigate the effects of interactions between PON1 variants and smoking on CHD in the Singaporean Chinese population.

      Methods

      In a case-control study nested within Singapore Chinese Health Study (N = 1914), subjects with and without CHD were classified into never-smokers and ever-smokers (ever smoked at least one cigarette a day for 1 year or longer). Associations at four independent SNPs at the PON1 locus (rs3735590, rs3917550, rs662, rs3917481) with CHD were evaluated using logistic regression, before/after stratification on smoking status. Interactions between smoking and PON1 variants were analyzed with likelihood ratio tests, by including the SNP*smoking interaction term in regression analyses.

      Results

      The T allele at the coding SNP, rs662, was associated with higher risk of CHD in ever-smokers only (OR = 1.35, 95% CI 1.08–1.68; adjusted P = 0.036). At the miR-SNP, rs3735590, carrying at least one copy of minor allele T was associated with increased risk of CHD in a dominant manner in never-smokers only (OR = 1.53, 95% CI 1.11–2.11; adjusted P = 0.036). Significant interactions between two PON1 SNPs and smoking in relation to CHD risk were identified (adjusted P = 0.012 for rs662; adjusted P = 0.044 for rs3735590). These associations remained significant after adjustment for known CHD risk factors and upon correction for multiple tests.

      Conclusions

      Two PON1 SNPs, rs662 and rs3735590, were found to significantly interact with cigarette smoking to modulate the risk of CHD in the Singaporean Chinese population.

      Keywords

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