Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/cca Paraoxonase 1 (PON1)-L55M among common variants in the coding region of the paraoxonase gene family may contribute to the glycemic control in type 2 diabetes Abdolkarim Mahrooz a,b,c, ⁎ ,1 , Mohammad Bagher Hashemi-Soteh b,c,1 , Masoud Heydari c , Ruzbeh Boorank c , Fatemeh Ramazani c , Ali Mahmoudi c , Anvarsadat Kianmehr d , Ahad Alizadeh e, ⁎⁎ a Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran b Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran c Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran d Department of Medical Biotechnology, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran e Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran ARTICLE INFO Keywords: Paraoxonase PON1 PON2 PON1-L55M Glycemic control Type 2 diabetes ABSTRACT Objective: Genome studies have shown that the genes encoding paraoxonase 1 (PON1) and PON2 are associated with glucose metabolism. The goal of this study was to simultaneously evaluate the association between func- tional variants in PON1 and PON2 genes and susceptibility for type 2 diabetes (T2D) and determine whether they can affect glycemic control. Methods: We performed a case-control study with 145 newly diagnosed patients with T2D and 148 controls. The common variants including PON1-Q192R, PON1-L55M and PON2-S311C were genotyped by PCR-based RFLP. A mismatch-PCR/RFLP was applied for genotyping the PON2-A148G variant. Results: The variant PON1-Q192R in males (OR = 2.55, 95%CI 1.16–5.69, p = 0.023) and PON2-A148G in fe- males (OR = 1.56, 95%CI 1.00–2.44, p = 0.059) were associated with T2D. Compared with the LL genotypes of PON1-L55M, HbA1c levels were significantly lower in the LM genotypes (p = 0.01) and MM genotypes (p = 0.032) in patients. Multiple linear regression analyses showed that among the study variants only the PON1-L55M variant as an independent variable significantly associated with glycemic control. This variant significantly influenced glycemic control in patients with poor glycemic control so that it was better with the following order: LL < LM < MM. Based on gamma correlation, there was a significant inverse association between the number of M alleles of the PON1-L55M and HbA1c levels (r = -0.261, p = 0.001). Conclusions: Sex should be considered a confounding variable in association studies on the variants PON1- Q192R and PON2-A148G in T2D. Patients sharing the 55 M allele were prone to having good glycemic control. Our findings provide genetic evidence that the PON1-L55M variant may be a factor contributing to glycemic control. 1. Introduction The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that are located adjacent to each other on the long arm of chromosome 7q21–22 in humans [1,2]. PON1 and PON3 are predominantly located in the circulation associated with high density lipoprotein (HDL) particles, while PON2 is an intracellular en- zyme and is not present in the circulation [2,3]. All three members of the family are important players in retarding the oxidative modification of low density lipoprotein (LDL) and cell membranes and, therefore, prevention of atherosclerosis [1,2]. PON1 (EC 3.1.8.1), as an atheroprotective and antioxidative enzyme can prevent oxidized-LDL (ox-LDL) production [4,5]. Oxidized phos- pholipids accumulate in PON1-deficient mice, and the animals are more prone to accelerate atherosclerotic lesions than control mice [4]. There are two common and functional single nucleotide variants in the PON1 gene: glutamine (Q) to arginine (R) substitution at codon 192 (Q192R; rs662) and leucine (L) to methionine (M) substitution at codon 55 https://doi.org/10.1016/j.cca.2018.05.037 Received 8 February 2018; Received in revised form 12 May 2018; Accepted 18 May 2018 ⁎ Corresponding author at: Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Km 17 Khazarabad Road, Sari, Iran. ⁎⁎ Corresponding author. 1 Co-first authors: Abdolkarim Mahrooz and Mohammad Bagher Hashemi-Soteh contributed equally to this research. E-mail addresses: amahrooz@mazums.ac.ir (A. Mahrooz), a-alizadeh@razi.tums.ac.ir (A. Alizadeh). Clinica Chimica Acta 484 (2018) 40–46 Available online 19 May 2018 0009-8981/ © 2018 Elsevier B.V. All rights reserved. T