CLINICAL STUDY Q192R polymorphism of the paraoxonase-1 gene as a risk factor for obesity in Portuguese women Luı ´sa Veiga 1, *, Jose ´ Silva-Nunes 1,2, *, Alice Mela ˜o 1 , Ana Oliveira 1 , Leone Duarte 2 and Miguel Brito 1 1 Escola Superior de Tecnologia de Sau ´de de Lisboa, Avenida D. Joa ˜o II, lote 4.69.01, Parque das Nac ¸o ˜es, 1990-096 Lisboa, Portugal and 2 Endocrinology Department, Curry Cabral Hospital, 1069-166 Lisbon, Portugal (Correspondence should be addressed to L Veiga; Email: luisa.veiga@estesl.ipl.pt) *(L Veiga and J Silva-Nunes contributed equally to this work) Abstract Introduction: Obesity became a major public health problem as a result of its increasing prevalence worldwide. Paraoxonase-1 (PON1) is an esterase able to protect membranes and lipoproteins from oxidative modifications. At the PON1 gene, several polymorphisms in the promoter and coding regions have been identified. The aims of this study were i) to assess PON1 L55M and Q192R polymorphisms as a risk factor for obesity in women; ii) to compare PON1 activity according to the expression of each allele in L55M and Q192R polymorphisms; iii) to compare PON1 activity between obese and normal-weight women. Materials and methods: We studied 75 healthy (35.9G8.2 years) and 81 obese women (34.3G8.2 years). Inclusion criteria for obese subjects were body mass index R30 kg/m 2 and absence of inflammatory/neoplasic conditions or kidney/hepatic dysfunction. The two PON1 polymorphisms were assessed by real-time PCR with TaqMan probes. PON1 enzymatic activity was assessed by spectrophotometric methods, using paraoxon as a substrate. Results: No significant differences were found for PON1 activity between normal and obese women. Nevertheless, PON1 activity was greater (P!0.01) for the RR genotype (in Q192R polymorphism) and for the LL genotype (in L55M polymorphism). The frequency of allele R of Q192R polymorphism was significantly higher in obese women (P!0.05) and was associated with an increased risk of obesity (odds ratioZ2.0 – 95% confidence interval (1.04; 3.87)). Conclusion: L55M and Q192R polymorphisms influence PON1 activity. The allele R of the Q192R polymorphism is associated with an increased risk for development of obesity among Portuguese Caucasian premenopausal women. European Journal of Endocrinology 164 213–218 Introduction Serum paraoxonase-1 (PON1, E.C.3.1.8.1) is a glycosy- lated protein of 355 amino acids, with a molecular mass of 43–47 kDa. It is synthesized by the liver and secreted into the blood, where it circulates in association with high-density lipoprotein cholesterol (HDLc) (1, 2). PON1 is a calcium-dependent esterase known for its ability to hydrolyze active metabolites of several organophosphates (3, 4). Its primary physiological role is the protection of low-density lipoprotein cholesterol (LDLc) and HDLc from oxidative modifications through enzymatic hydroxylation of oxidized phospho- lipids (1, 4–6). The enzymatic activity of PON1 varies widely among healthy humans, and it has been suggested that subjects with low PON1 activity may have a greater risk of developing diseases in which oxidative damage and lipid peroxidation are involved (2, 3, 7). Several studies have demonstrated that the antioxidant activity of PON1 prevents oxidative stress mechanisms involved in pathophysiological processes associated with athero- sclerosis and diabetes mellitus, among other common pathologies (8–11). PON1 activity is modulated by environmental compounds and lifestyle, but also by genetic polymorphisms (7, 12). Human PON1 gene is coded on chromosome 7q21.3–22.1, and several polymorphisms have been identified on its promoter and coding regions. Two polymorphisms in the coding region of PON1 gene have been identified and widely studied: non-synonymous amino acid substitution Gln 192 /Arg (Q192R) and Leu 55 /Met (L55M) (12, 13). The presence of each of these polymorph- isms has shown to lead to different PON1 phenotype. The presence of L55M (rs854560) has been associ- ated with changes in the concentration of the enzyme but small effects on its activity. On the other hand, the polymorphism Q192R (rs662) leads to different PON1 enzymatic activity behavior dependent of the isoenzyme that is present (4). These polymorphism-dependent European Journal of Endocrinology (2011) 164 213–218 ISSN 0804-4643 q 2011 European Society of Endocrinology DOI: 10.1530/EJE-10-0825 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 05/31/2020 09:41:37PM via Massachusetts Inst of Technology