{"paper_id":"b257b4d9-7e33-4016-8f6f-f14baeb363b7","body_text":"Asian Pacific Journal of Cancer Prevention, Vol 20\n2595\nDOI:10.31557/APJCP .2019.20.9.2595\nACE and AGTR1 Polymorphisms and Uterine Leiomyoma \nAsian Pac J Cancer Prev, 20 (9), 2595-2599 \nIntroduction\nUterine leiomyomas (ULs) can be considered as the \nmost common benign monoclonal tumors of the smooth \nmuscle cells in the myometrium (Flynn et al., 2006). \nEvidence suggests that 70% of women may develop \nuterine fibroids. Although this disorder may be without \nsigns and symptoms, in 40 to 50 percent of women over \nage 35 it may present as menorrhagia, infertility, pain, and \nrecurrent pregnancy loss (RPL) (Marino et al., 2004; Wang \net al., 2015). There are different risk factors influencing \nthe growth of UL, including: ethnicity, smoking, family \nhistory, obesity, diet rich in meat, oral contraceptive pills, \nage, and biological biomarkers (Faerstein et al., 2001; \nKeshavarzi et al., 2017). Despite the various studies \nconducted to understand UL etiology, the exact mechanism \nof UL pathogenesis is not yet known clearly (Strawn et \nal., 1995). Several mechanisms have been suggested \nthat have the effects on growth of UL, including ovarian \nangiogenesis, steroid hormones, growth factors, and \nAbstract\nObjective: Uterine leiomyoma (UL) can be considered as the most common benign gynecological tumors of \nthe smooth muscle cells in the myometrium. They are likely to be associated with infertility and recurrent abortion \nas well as obstructed labor and post-partum hemorrhage. Moreover, altered vascular-related genes can be linked to \ndeveloping leiomyoma. Polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with some \nvascular diseases. The present study was carried out to investigate the association of ACE I/D and AGTR1 A1166C \ngene polymorphisms and the risk of uterine leiomyoma in a sample of Iranian population. Methods: The study was \ncarried out on a total of 413 women divided into 202 patients with diagnosed uterine leiomyomas and a control group \nof 211. Genotyping was performed using the PCR or PCR-RFLP methods. Results: The ID and DD genotypes of ACE \nI/D polymorphism were associated with 2 and 2.9 fold higher risk of UL compared to II genotype (OR, 2 [95% CI, \n1.3 to 3.2]; P = 0.004 and OR, 2.9 [95% CI, 1.6 to 5]; P = 0.0002). The frequencies of ACE D alleles were 53.7% in \nwomen with UL and 40.3% in controls, which were observed to be statistically different (P < 0.0001). The alleles and \ngenotypes of AGTR1 A1166C polymorphism were not different between UL and control women (P=0.9). Conclusion: \nThe ACE ID and DD genotypes were associated with a higher risk of UL. No relationship was found between AGTR1 \nA1166C polymorphism and UL.\nKeywords: ACE- AGTR1- polymorphism- uterine leiomyoma\nRESEARCH ARTICLE\nAssociation of ACE I/D and AGTR1 A1166C Gene Polymorphisms \nand Risk of Uterine Leiomyoma: A Case-Control Study\nFarshid Keshavarzi 1,2, Batool Teimoori 3,4, Farahnaz Farzaneh 3, Mojgan \nMokhtari5, Darya Najafi6, Saeedeh Salimi1*\napoptosis related factors (Wang et al., 2002).\nBoth abnormal angiogenesis and vascular-related \ngrowth factors have been considered to be associated \nwith the UL pathogenesis and growth. Growth factors \nmay typically stimulate the angiogenesis of leiomyoma \ncells as compared with adjacent normal cells (Boehm et \nal., 1990; Di Lieto et al., 2005). Numerous investigations \nhave revealed that both chromosome abnormalities in UL \npatients as well as genetic factors play key roles in UL \npathogenesis in different countries, such as Iran (Gan \net al., 2015; Salimi et al., 2015; Yaghmaei et al., 2015; \nSalimi et al., 2016). It is believed that ACE activity may \nbe related to tumor growth and ACE inhibitors as well as \nangiotensin receptor blockers, thereby contributing to the \nsuppression of tumor growth.\nThe renin-angiotensin system (RAS) may be \nconsidered as an essential pathway in the regulation of \nblood pressure and electrolyte balance. Independent tissue \nrenin angiotensin systems (RASs) have been demonstrated \nin many organs including heart, kidney, brain, adrenal \nEditorial Process: Submission:07/13/2018   Acceptance:09/09/2019\n1Department of Clinical Biochemistry, 3Department of Obstetrics and Gynecology,  School of Medicine, 2Cellular and Molecular \nResearch Center, 4Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, 5Department of Obstetrics \nand Gynecology, School of Medicine, 6Medical College, Iran University of Medical Sciences, Tehran,  Iran. *For Correspondence: \nsasalimi@yahoo.com\n\nFarshid Keshavarzi et al\nAsian Pacific Journal of Cancer Prevention, Vol 20\n2596\nglands, vasculature, and the uteroplacental unit (Kobori et \nal., 2007). In this pathway, the angiotensin peptide binds to \nits related angiotensin receptors, angiotensin receptor type \n1 (AGTR1) and angiotensin receptor type 2 (AGTR2) to \nprompt various biological responses (Elton et al., 2010). \nAlthough several genes are selectively overexpressed \nin leiomyomas, compared to normal myometrium, such \nas insulin-like growth factor-2 receptor and insulin-like \ngrowth factor binding protein, the angiotensinogen gene \nas a member of renin-angiotensin system has been down \nregulated in these tissues. There is evidence showing that \nthat both ACE inhibition and AGTR1 blockade inhibit \ntumor angiogenesis, vascular density, tumor growth, \nreduced tumor volume, cell proliferation, and mitotic \nindex and they actually reduce metastasis, too.\nSince the effects of polymorphisms may be reversed \nor antagonized using medical treatment, they can be used \nto reduce or to inhibit tumor development (Hortobagyi, \n2012). It has been shown that AGTR1 protein is expressed \nin benign states, such as ovarian cyst adenomas, and is \ninvolved in angiogenesis and tumor progression. It is also \nreported to be expressed in several cancers, including \nthe breast (Herr et al., 2008), bladder (Kosugi et al., \n2006), gastric (Röcken et al., 2007), pancreatic (Amaya \net al., 2004), prostate (Uemura et al., 2006), endometrial \n(Watanabe et al., 2003), and renal cancers as well as ovarian \ncarcinoma (Suganuma et al., 2005). Angiotensin type 1 \nreceptor is mostly up regulated during the progression \nfrom normal to malignant phenotypes, indicating a \nrelationship between the RAS and tumor progression at \nthe very least. The angiotensin converting enzyme (ACE; \nEC 3.4.15.1), a dipeptidyl carboxy peptidase, is encoded \nby the ACE gene, which is located on chromosome 17q23 \nand includes 25 introns and 26 exons (Sayed-Tabatabaei \net al., 2006a). ACE enzyme, which catalases conversion \nof the inactive angiotensin I to the angiotensin II, exerts \nmost of its effects via the activation of AGTR1 receptors \nexpressed in vascular smooth muscle cells and adrenal \nglands, among others (Irani and Xia, 2008).\nThere is an insertion/deletion polymorphism ( I/D) \nof a 287 bp in the intron 16 of ACE gene, with its DD \ngenotype, which may be associated with elevated plasma \nand serum ACE levels as compared to heterozygous ID \nand homozygous II genotypes. In addition, the A to C \npolymorphism in the 3ˊ-’untranslated region at nucleotide \n1,166 of the AGTR1 gene has been identified and described \nin association with various diseases.\nAs the role of RAS system has been characterized \nin tumor development, the aim of the present study was \nto investigate the association between the  ACE I/D, and \nA1166C polymorphisms and UL.\nMaterials and Methods\nSubjects\nA total of 413 pre-menopausal women including 202 \nuterine leiomyoma and 211 healthy controls were recruited \nin the current case-control study. The case and control \ngroups were matched according to age, ethnicity, and \nBMI. Participants were selected from among women who \nhad undergone myomectomy or hysterectomy and were \nconfirmed pathologically in Ali-ebn-Abitaleb Hospital. \nThe controls selected from among women referring \nfor routine check-ups who had no history of UL upon \nsonography or examination. UL women and controls had \nno history of malignancy and systemic diseases.\nEach research participant voluntarily provided her \ninformed consent with her peripheral blood sample. The \nproject protocols followed the principles stated in the \nDeclaration of Helsinki for medical research involving \nhuman subjects and received its prior approval from the \nEthics Committee of Zahedan University of Medical \nSciences (Code no. 8807). \nGenotype analysis\nGenomic DNA was extracted from 2 mL of peripheral \nblood leucocytes from all women for genetic analysis \nusing the salting out method. In the current study, \ntwo polymorphic sites were analyzed in both uterine \nleiomyoma and the control groups. \nGenotyping for I/D polymorphism of ACE gene\nTo determine the ACE I/D  gene polymorphism, a \ngenomic DNA fragments on intron 16 of the ACE gene \nwas amplified using PCR. Two oligonucleotide primers \n(forward) 5ˊ-CTG GAG AGC CAC TCC CAT CCT TTC \nT-3ˊ and (reverse) 5ˊ- GGG ACG TGG CCA TCA CAT \nTCG TCA G-3ˊ were used in a 20-μL final volume for each \namplification. Each PCR reaction consisted of an initial \ncycle at 94°C for 5 min, 30 cycles at 94°C for 30 s, 60°C \nfor 60 s, and 72°C for 60 s; followed by an extension at \n72°C for 10 min. The PCR products of two alleles of 490 \nbp and 190 bp were electrophoresed in 2% agarose gels, \nand visualized under ultraviolet (UV) light using ethidium \nbromide staining. A 190 bp fragment was produced in \nthe absence of an insertion (D) and a 490 bp fragment in \nthe presence of insertion (I). Thus, the homozygote DD \nproduced one band (190 bp), the homozygote II produced \none band (480 bp long), and the heterozygote ID produced \nboth bands (190 bp and 490 bp). The feedback yielded a \n335-bp amplicon only in the existence of an I allele and \nno product in homozygous for DD.\nGenotyping for the A1166C polymorphism of AGTR1 gene\nThis polymorphic site was genotyped using polymerase \nchain reaction-restriction fragment length polymorphism \n(PCR-RFLP) method. The primers used to amplify DNA \nfragment, encompassing the A1166C polymorphism \nincluded 5ˊ-AAT GCT TGT AGC CAA AGT CAC CT-3ˊ \nand (reverse) 5ˊ-GGC TTT GCT TTG TCT TGT TG-3ˊ to \nproduce a fragment of 856 bp. PCR was performed in a \n20 μl final volume. After an initial melting step at 94°C \nfor 5 min, the PCR procedure (consisting of 35 steps) was \ncarried out followed by denaturation at 94°C for 30 s, \nannealing at 57 °C for 30 s, and extension at 72°C for 60s, \nand a final extension step at 72°C for 5 min. The amplified \nfragment was cut via Dde1 restriction enzyme (Fermentas, \nLithuania) at 37°C for 16 h. The wild-type allele (A allele) \nhad one Dde1 cleavage site and digested to 600 and 256 \nbp fragments, whereas the mutant allele (C allele) had two \nDde1 cleavage sites and 256 bp fragment was cleaved to \n146 and 110 bp fragments, too. Digested products were \n\nAsian Pacific Journal of Cancer Prevention, Vol 20\n2597\nDOI:10.31557/APJCP .2019.20.9.2595\nACE and AGTR1 Polymorphisms and Uterine Leiomyoma \nrisk with a number of studies investigating the association \nbetween the polymorphisms of various genes in RAS \npathway and tumorigenesis (Deshayes and Nahmias, \n2005). \nIn the current study, we investigated two common \npolymorphisms in RAS pathway and reported their effects \non tumorigenesis. The evidence showed that the ACE D \nallele increases the enzyme activity and higher activity \nof ACE enzyme was observed in individuals with DD \ngenotype (Sayed-Tabatabaei et al., 2006b). In addition, \nit is suggested that AGTR1 A1166C  is located in the \nmicroRNA-155 binding site and the A allele increases \nits affinity, leading to lower AGTR1 protein expression \n(Ceolotto et al., 2011).\nIn the current study, the frequencies of the ACE ID \nand DD genotypes were significantly higher in women \nwith UL. Also, these genotypes were associated with \nthe 2 and 2.9 fold increased risk of UL, respectively. \nHowever, there was no association between AGTR1 \nA1166C polymorphism and UL.\nAlthough many studies have reported the association \nbetween ACE I/D and AGTR1 A1166C polymorphisms and \nvarious diseases (Salimi et al., 2011; Gan et al., 2015), the \nnumber of studies conducted on the association between \nACE I/D and AGTR1 A1166C polymorphisms and UL are \nlimited with inconsistent results. \nIn spite of the findings of the present study, Salwa et al \nshowed the association between AC and CC genotypes of \nA1166C polymorphism in AGTR1 gene and the increased \nrisk of UL. Indeed, they reported no relationship between \nACE I/D  polymorphism and this tumor (Gomaa et al., \n2015). Similarly, Gültekin et al found no association \nbetween ACE I/D  polymorphism and UL in Turkish \npopulation (Gultekin et al., 2015). Hsieh et al. reported that \nACE I-related (II and ID) genotypes were associated with \nleiomyoma susceptibilities in Taiwan which is completely \ninconsistent with our results (Hsieh et al., 2007). In an \nexperimental study, Isobe et al. investigated the potential \nrole of Ang II in the proliferation of rat ELT-3 leiomyoma \ncells (Eker rat uterine leiomyoma-derived smooth \nmuscle cells) in vitro and found that Ang II significantly \nseparated via electrophoresis in a 2% agarose gel and \nvisualized using safe stain staining.\nResults\nDemographic and clinical characteristics of women \nwith UL and healthy controls are presented in Table1. \nThere was no statistically significant difference between \nmaternal age and menarche age between the two groups. \nAs expected, there were significant differences between \nthe case and control groups in terms of pain and bleeding \n(P<0.0001). \nThe frequencies for the distribution of alleles and \ngenotypes of ACE I/D and AGTR1 A1166C polymorphisms \nare summarized in Table 2.\nThe genotypes frequencies of the ACE I/D and AGTR1 \nA1166C polymorphisms conformed to Hardy–Weinberg \nequilibrium. Also, the frequencies of II, ID, and DD \ngenotypes were 20.8, 51, and 28.2 percent in UL women \nand 37, 45.5, and 17.5 in healthy women, respectively. \nMoreover, the risk of UL were 2 and 2.9 fold higher in ID \nand DD genotypes compared to II genotype, respectively \n(OR, 2 [95% CI, 1.3 to 3.2]; P = 0.004 and OR, 2.9 [95% \nCI, 1.6 to 5]; P = 0.0002). In addition, the frequency \nof D allele was 53.7% in women with UL and 40.3% \nin controls; the difference was found to be statistically \nsignificant (P = <0.0001). \nIn addition, the frequencies of AGTR1 1166AA, AC, \nand CC genotypes were 86.6, 13.4, and 0 percent in \nUL women and 86.2, 13.3, and 0.5 in healthy women, \nrespectively, which were not found to be statistically \nsignificant. The frequency of AGTR1 1166C allele did \nnot differ between two groups, either (P=0.9)\nDiscussion\nUterine leiomyomas (ULs) are the most common \ntumors in women, with its related etiopathogenes \nremaining unclear so far. Evidence showed a genetic \nbackground for UL. The incidence of various ULs \nconfirms a genetic predisposition for UL development. \nIn addition, the risk of UL is about 2.5 fold higher in \nthe first-degree relatives of women with these types of \ntumor (Boehm et al., 1990). Therefore, several studies \ninvestigated the effects of genetic polymorphisms on UL \nUL women\n(n=202)\nControls\n(n=211)\nP -value\nMaternal age (years) 38.8±9.9 38.3±7.8 NS\nMarriage status, n (%) 188 (93) 203 (96) NS\nBMI (Kg/m2) 25.9±5.5 25.1±4.4 NS\nAge of menarche (years) 13.6± 1.7 13.2±1.4 NS\nDuration of menses (days) 6.2±1.7 5.8±1.6 NS\nMenstrual cycle (days) 28.3± 3.5 28.5±2.8 NS\nBleeding, n (%) 121 (60) 7 (3) <0.0001\nPain, n (%) 58 (29) 13 (6) <0.0001\nGenotypes/\nAlleles\nUterine \nLeiomyoma \n (n=202)\nControl \n(n=211)\nP-value OR \n (95% CI)\nACE I/D\nII 42 (20.8) 78 (37) 1\nID 103 (51) 96 (45.5) 0.004 2 (1.3 –3.2)\nDD 57 (28.2) 37 (17.5) 0.0002 2.9 (1.6-5)\nI 187 (46.3 ) 252 (59.7) - -\nD 217 (53.7) 170 (40.3) <0.0001 1.7 (1.3-2.3)\nAGTR1 A1166C\nAA 175 (86.6) 182 (86.2)\nAC 27 (13.4) 28 (13.3) 1 1 (0.6-1.8)\nCC 0 (0) 1 (0.5) - -\nA 377 (93.3) 392 (92.9)\nC 27 (6.7) 30 (7.1) 0.9 0.9 (0.6-1.6)\nNS, (not significant); UL, (uterine leiomyoma)\nTable 1. Clinical and Demographic Characteristics of \nUL Women and Control Group\nTable 2. The Allelic and Genotypic and Frequencies of \nACE I/D  and Angiotensin II Type-1 Receptor A1166C \nPolymorphisms in UL Women and Controls\n\nFarshid Keshavarzi et al\nAsian Pacific Journal of Cancer Prevention, Vol 20\n2598\ninduced ELT-3 leiomyoma cell proliferation and the \nexpression of AGTR1 and AGTR2 mRNA and protein \nwas confirmed. These experimental in vitro findings \nhighlight the potential role of Ang II, through AGTR1 in \nthe proliferation of leiomyoma cells (Isobe et al., 2007).\nSeveral studies have investigated the effects of \nACE and AGTR1 polymorphisms on various tumors \nwith inconsistent results. Kowalczyńska et al., (2011) \nfound no association between ACE I/D  polymorphism \nand the prevalence of endometriosis in polish women \n(Kowalczyńska et al., 2011). In another study conducted in \n2014, these authors reported that A2350G polymorphism \n(G allele and AG genotype) of ACE gene but not ACE \nI/D and AGTR1 A1166C polymorphisms was associated \nwith the development of endometriosis (Kowalczyńska \net al., 2014).\nIn addition, other studies showed the association \nbetween ACE I/D and AGTR1 A1166C polymorphisms \nand various cancer risks including breast cancer (Herr \net al., 2008), prostatic cancer (Uemura et al., 2006), \nand gastric cancer (Röcken et al., 2007). Although, our \nfindings are not similar to those reported by Salwa et al and \nHsieh et al., they are in accordance to the effect of higher \nACE activity on tumorigenesis and ACE DD genotype on \nhigher ACE activity. \nIn conclusion, for the first time in Iranian women, \nthe current study showed ACE ID and DD genotypes \nwere associated with higher UL risk and that there is no \nrelationship between A1166C polymorphism of AGTR1 \ngene and UL. 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Association of \nXRCC1 Arg399GIn and Tp53 Arg72Pro polymorphisms and \nincreased risk of uterine leiomyoma - A case-control study. \nGenet Mol Biol, 38, 444-9.\nThis work is licensed under a Creative Commons Attribution-\nNon Commercial 4.0 International License.","source_license":"CC0","license_restricted":false}