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  • CARIPORIDE Indeed some studies that examined the morphine


    Indeed, some studies that examined the morphine response have reported that the (C) allele of rs4818 was associated with a low dose administered compared to that given for individuals with the (G) allele (Rakvag et al., 2008). In a publication about Tunisian patients with cancer by Chatti et al. (2016), where rs4860 was analyzed to study the response to morphine (Chatti et al., 2016), results have shown no association. Interestingly, the patients are from three main Tunisian regions (Tunis, Sousse, and Sfax). The authors of this study pooled all the samples. For comparison, we also pooled our Tunisian populations and showed that allelic frequencies of the Tunisian patients (Chatti et al., 2016) and healthy Tunisians population (the present study) are the same, but there is a small difference for genotype frequencies with an excess of heterozygous for the healthy individuals (Table 5). The population of Sousse presents allelic and genotypic frequencies different from the two pooled samples due to its genetic structure that distinguishes it from other populations of North Africa. Hence pooling it with other populations might constitute a bias for results in the analysis which may explain the absence of an association with the response with morphine. This study on population genetics of the COMT gene polymorphism highlights the importance of considering very precise geographic origin of subjects, along with age and sex in cases/controls studies performed in Tunisia since pooling of heterogeneous populations can result in false positives and false negatives. Indeed, the Tunisian population is a mosaic of sub-populations, each CARIPORIDE displaying its own genetic structure due to high level of endogamy practiced in this country (Cherni et al., 2016).
    Conclusions The following are the supplementary data related to this article.
    Declaration of interests
    Acknowledgments This work was partially supported by the Tunisian Ministry of Higher Education and Scientific Research as well as by the University of Tunis El Manar. Special thanks go to the thousands of individuals around the world who volunteered to give blood and saliva samples to made this study possible.
    Introduction Breast cancer (BCa) is the most commonly diagnosed cancer among women in the United States ( Endogenous estradiol (E2) is suggested to be one of the major risk factors for BCa (Travis and Key, 2003). Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of E2/estrone (E1) catechols which blocks their estrogenicity and further oxidation to reactive quinones that form mutagenic depurinating DNA adducts and also oxidative DNA damage through redox cycling (Lavigne et al., 2001; Yager, 2015; Cavalieri and Rogan, 2016). Inhibition of COMT enzyme activity has been shown to enhance oxidative DNA damage and adenine and guanine adduct levels in MCF-7 and MCF-10F cells treated with E2 and 4-OH E2 (Lavigne et al., 2001; Zahid et al., 2007). It suggest that a “gate keeper” role for O-methylation by COMT by preventing further E2/E1 catechol oxidative metabolism. Genetic variations of COMT were shown to be associated with BCa risk (reviewed by Yager, 2012), suggesting the potential role of COMT in development of BCa. The COMT gene, located on chromosome 22, contains CARIPORIDE six exons and encodes membrane-bound (MB) and cytosolic (S) forms of the enzyme regulated by two promoters. Promoter 1 regulates expression of the 1.3 kb mRNA encoding S-COMT, a 24kd cytosolic protein and promoter 2 regulates expression of a 1.5 kb mRNA containing non-coding exons 1 and 2 and encoding MB-COMT, a 30kd membrane-bound protein (Yager, 2012). The additional N-terminal region in MB-COMT contains membrane anchoring hydrophobic amino acids (Zhu, 2002). MB-COMT is localized to the endoplasmic reticulum and variably on the plasma membrane and nuclear envelope in a variety of cell types (Tilgmann et al., 1992; Ulmanen et al., 1997) and in breast epithelial normal and tumor tissue (Weisz et al., 2000).