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Association of CYP11B2 gene polymorphism with preeclampsia in north east of Iran (Khorasan province)
Journal Pre-proofs Research paper Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province) Mohsen Azimi-Nezhad, Atieha Teymoori, Reza Ebrahimzadeh-Vesal PII: DOI: Reference:
S0378-1119(20)30027-5 https://doi.org/10.1016/j.gene.2020.144358 GENE 144358
To appear in:
Gene Gene
Received Date: Revised Date: Accepted Date:
20 June 2019 7 January 2020 8 January 2020
Please cite this article as: M. Azimi-Nezhad, A. Teymoori, R. Ebrahimzadeh-Vesal, Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province), Gene Gene (2020), doi: https://doi.org/ 10.1016/j.gene.2020.144358
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier B.V.
Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province)
Mohsen Azimi-Nezhad1, Atieh Teymoori2, Reza Ebrahimzadeh-Vesal3,4*
1. Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2- Department of Medical Genetics, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. 3- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. Electronic address: [email protected]. 4-Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, IRAN.
Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province)
Mohsen Azimi-Nezhad1, Atieh Teymoori2, Reza Ebrahimzadeh-Vesal3,4*
1. Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2- Department of Medical Genetics, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. 3- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. Electronic address: [email protected]. 4-Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, IRAN. * Corresponding author: Reza Ebrahimzadeh-Vesal
Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. [email protected] [email protected]
Abstract Abstract Purpose: Identification the genetic factors in preeclampsia (PE) are useful to increase the current knowledge of the pathophysiology of the disorder. The genetic factors implicated for all cases of PE remain to be determined. This study was aimed to investigate association between ADD1 1378G>T, AGTR2 1675G>A, AGTR1 1166A>C, NOS3 894 G>T and CYP11B2 -344C>T gene polymorphisms in Iranian women with PE.
Material and Methods: 117 pregnant women with PE and 103 healthy women without affected previous pregnancy by PE were selected. Genomic DNA was extracted from peripheral blood and realtime PCR was performed to investigate the polymorphisms using a commercial kit.
Results: There was a significant difference in CYP11B2 -344C>T gene polymorphism between case and control groups (P=0.025). The odds ratio was 0.71 (CI 95% = 0.28-1.79). There were no statistical significant differences between other genetic polymorphisms.
Conclusion: Our results showed a significant association between CYP11B2 -344C>T gene polymorphism with PE. This finding suggests that mentioned polymorphism may be associated with susceptibility to PE at least in IRAN.
Keywords: Preeclampsia, polymorphism, CYP11B2, NOS3, ADD1, AGTR1, AGTR2
1. Introduction Preeclampsia is one of the most common complications of pregnancy which characterized by proteinuria and high blood pressure in second half of pregnancy. It is one of the main causes of maternal and fetal morbidity and mortality. Its prevalence is about 5-8% of all pregnancies worldwide. Usually and about 20-25% of women with a history of chronic hypertension develop PE (Hutcheon et al., 2011; Mohaupt, 2007; Pettit and Brown, 2012; Sibai et al., 2005; Tranquilli et al., 2012; Xia and Kellems, 2009). HELLP syndrome is a severe form of pregnancy complication characterized by hemolysis (H), elevated liver enzymes (EL) and low platelets (LP). This syndrome has a significant contribution to maternal and fetal mortality (Eiland et al., 2012; Mohaupt, 2007; Mutter and Karumanchi, 2008). Unfortunately, there is currently no definitive treatment for women with PE. Prevention of PE is controversial and a health care control during pregnancy is recommended for the prevention of this disorder. The exact cause of the disorder is still unknown. Several studies suggest that immunologic factors, coagulation disorders, nutritional factors, and also reactive oxygen radicals can develop PE (Broughton Pipkin and Rubin, 1994; Chaouat et al., 2003; Hung and Burton, 2006; Maine, 2000; Savelieva et .al., 1995) Preeclampsia has no clear mode of inheritance and different genetic variants are associated with susceptibility to this disorder. However, PE is a complex genetic disorder and the main genetic .causes of PE has not been elucidated yet (Bernard and Giguere, 2003) Alpha adducin (ADD1) is one of the candidate gene for essential hypertension(Casari et al., 1995; Matsuoka et al., 2000; Tripodi et al., 1996). Epidemiological studies have been shown association of ADD1 1378G>T polymorphism with hypertension in different populations (Iwai et al., 1997; Kamitani et al., 1998; Manunta et al., 1998).
Angiotensinogen protein is an important part of the Renin–angiotensin (RA) system which encoded by angiotensin gene (AGT). Renin-angiotensin Aldosterone system, RAAS, is the most important system for regulation of salt metabolism and control of blood pressure. It has been suggested that several single nucleotide polymorphisms in associated genes with RA system, may has an important role in the regulation of hypertension and pathogenicity of PE (Choi et al., 2004). Nitric oxide synthase 3 (NOS3) is located on the long arm of chromosome 7 and its protein has a function in the regulation of blood pressure(Southan and Szabo, 1996). Previous studies showed association of NOS3 -894G>T (rs1799983) polymorphism with blood pressure (Hingorani et al., 1999; Wang et al., 1996). The CYP11B2 gene is located on the long arm of chromosome 8 and provides instructions for making an enzyme called aldosterone synthase (Shojaati et al., 2004; White and Slutsker, 1995). Previous studies showed that -344T/C polymorphism in the promoter region of human CYP11B2 gene is associated with genetic predisposition to hypertension (Tsukada et al., 2002). The overall prevalence of PE in Iranian population is about 5%. In this study we examined the association of ADD1 1378G>T (rs4961), AGTR2 1675G>A (rs1403543), AGTR1 1166 A>C (rs5186), NOS3 +894 G>T (rs1799983) and CYP11B2 -344C>T (rs1799998) gene polymorphisms with PE in a population of Iranian women. 2. Material and Methods 2.1. Sample preparation This case-control study was performed on 117 women with a diagnosis of PE (blood pressure>140/90 mmHg and proteinuria> 0.3 g in 24 hours urine samples after 20 weeks of pregnancy) in the case group and 103 normotensive women with at least one normal pregnancy without history of PE in the control group. The mean age of case samples was 28.5 years (From 20 to 37 ages) and all of the cases samples had singleton pregnancy. The women in case and control groups were normotensive before pregnancy. About 35% of case samples and 25% of control samples had consanguineous marriage. The samples were collected from May 2017 and March 2018 in Neyshabur Hakim hospital in the Razavi Khorasan province. This research has been approved by ethics committee of Neyshabour University of Medical Sciences (IR.NUMS.REC.1396.1). Written consent was obtained from all the participants in the study.
2.2. DNA extraction and genotyping The genomic DNA was extracted from peripheral blood using high pure PCR template preparation kit (Roche) according to the manufacturer's protocol. Genotyping was performed using real-time PCR hypertension SNP kit according to the manufacturer's protocol. (DNATechnology, Russia). All real-time PCR reactions were carried out in duplicate in DT-Prime 4 color real-time PCR thermocycler (DNA-Technology, Russia). Genotypes of SNPs were determined based on simultaneous hybridization of two alternative sequence-specific typing probes labeled with different fluorophores using melting curve analysis according to protocol guideline. 2.3. Statistical Analysis Statistical analysis was performed using the SNP stats online software. The comparison of the allele and genotype frequencies between patient and control groups was performed using chisquare and t-test by the SPSS software (version 19). The p-values less than 0.05 were considered statistically significance.
3. Results The analysis of CYP11B2 -344C>T polymorphism showed a significant differences between homozygous TT (12.8% vs 20.4%) and heterozygous CT genotypes (64.9% vs 52.4%) in the case and control groups, respectively (p value=0.025, OR =0.71, CI 95% = 0.28-1.79) (Table 1). The analysis of ADD1 1378G>T gene polymorphism was not significantly different between homozygous TT (10.2% vs. 3.9%), heterozygous GT (15.5% vs 13.6%) and homozygous GG genotypes (74.3% vs 82.5%) in the case and control groups respectively (Table 1). There were no significant differences in the frequency of ADD1 G (82% vs. 89.4 %) and T alleles (18% vs 10.6%) in both case and control groups (Table 2). Analysis of AGTR2 1675G>A in the case and control groups did not show a significant differences between homozygous AA (35.9% vs 21.4%), heterozygous AG (53% vs 44.7%) and homozygous GG genotypes (11.1% vs 33.9%) (Table1). Frequency of G allele (37.6 % vs 56.4 %) and A allele was (62.4% vs 43.6 %) similar in the case and control groups, respectively (Table 2). The analysis of AGTR1 1166 A>C polymorphism showed no significant differences
between homozygous CC (1.7% vs 2.9%), heterozygous AC (32.5 % vs 21.4%) and homozygous AA (65.8% vs 75.7%) in the case and control groups (Table 1). There was no significance difference in the frequency of A allele (82% vs 86.4%) and C allele (18% vs 13.6%) between both groups (Table 2). The analysis of NOS3 +894 G>T polymorphism showed no significant differences between homozygous TT (1.7% vs 2.9%), heterozygous GT (30.7% vs 36.9%) and homozygous GG (67.6% vs 60.2%) genotypes in both case and control groups (Table 1). Frequency of G allele (83% vs78.6%) and T allele (17% vs. 21.4%) did not show significant differences (Table 2).
4. Discussion Preeclampsia is a complex multifactorial disorder influenced by both genetic and environmental factors. Interaction of multiple genetic and environmental factors is known in the etiology of PE. Hypertension during pregnancy is one of the major causes of PE. Preeclampsia is one of the main causes of maternal and fetal morbidity. Many researchers studied genetic variants with putative effects on PE in different populations. CYP11B2 gene codes for a member of the cytochrome P450 family of enzymes which called aldosterone synthase. Aldosterone is the major mineralocorticoid hormone to regulate of blood pressure in human. Polymorphisms in associated genes in RAAS system may have effects on blood pressure. Hypertension is well known as one of the major components of PE. Previous study showed that -344 C allele binds to SF-1 four times more than the T allele which is associated with increased serum aldosterone level (White and Slutsker, 1995). The -344C>T polymorphism in the promoter region of CYP11B2 gene is a putative binding site for steroidogenic transcription factor1 (SF-1). An alteration on aldosterone synthase gene (CYP11B2) expression may be responsible as one of the causes of hypertension and then predisposition to PE. In the present case-control study, the frequency of heterozygous C/T genotypes in women with PE was statistically higher than the control group. Therefore, this polymorphism may be a risk factor for PE at least in the Iranian population. In another study, in Turkish population, no association between the CYP11B2 gene polymorphism and PE has been reported (Percin et al., 2006). Analysis of 344C>T polymorphism of CYP11B2 gene in women with PE in Caucasian population showed that frequency of TT genotype was significantly higher
in patients than in controls and they concluded that this polymorphism may be associated with developing PE during pregnancy(Bogacz et al., 2016). Analysis of CYP11B2 (C-344T) gene polymorphism in 603 South African Black pregnant women showed that the CT genotype was statistically significant between normotensive and PE groups(Aung et al., 2018). Frequency of 344T/C polymorphism on one hundred Mexican women was similar in the hypertensive and normotensive pregnant women and suggested that genotype of -344T/C of CYP11B2 was neither related with gestational hypertension nor with aldosterone levels at delivery.(Ramirez-Salazar et al., 2011). This lack of reproducibility between our data and other studies somehow may be explained by population diversity. We have detected no association between genotype and allele frequencies of ADD1 1378G>T, AGTR2 1675G>A, AGTR1 1166 A>C and NOS3 894 G>T polymorphisms with PE. These variants need to further studies in different populations to elucidate their putative function to develop of hypertension and PE. 7 Some imitations of this study include the relatively small number of the participants. This may be reduced the power of study to detect associations. Also, discrepancy in allele and genotype frequencies with Hardy– Weinberg equilibrium (HWE) may be explained with consanguineous marriage in some of the case and control samples.
Acknowledgment This study was approved and funded by a grant from Neyshabur University of Medical Sciences. Number of approval was IR.NUMS.REC.1396, thesis code: 203. We also thank participants in this study. Conflict of interest All authors declare no conflict of interests
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S.B., 1998. Human alpha-adducin gene, blood pressure, and sodium metabolism. Hypertens. (Dallas, Tex. 1979) 32, 138–143. Maine, D., 2000. Role of nutrition in the prevention of toxemia. Am. J. Clin. Nutr. 72, 298S– 300S. https://doi.org/10.1093/ajcn/72.1.298S Manunta, P., Cusi, D., Barlassina, C., Righetti, M., Lanzani, C., D’Amico, M., Buzzi, L., Citterio, L., Stella, P., Rivera, R., Bianchi, G., 1998. Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients. Kidney Int. 53, 1471–1478. https://doi.org/10.1046/j.1523-1755.1998.00931.x Matsuoka, Y., Li, X., Bennett, V., 2000. Adducin: structure, function and regulation. Cell. Mol. Life Sci. 57, 884–895. https://doi.org/10.1007/PL00000731 Mohaupt, M., 2007. Molecular aspects of preeclampsia. Mol. Aspects Med. 28, 169–191. https://doi.org/10.1016/j.mam.2007.02.005 Mutter, W.P., Karumanchi, S.A., 2008. Molecular mechanisms of preeclampsia. Microvasc. Res. 75, 1–8. https://doi.org/10.1016/j.mvr.2007.04.009 Percin, F.E., Cetin, M., Pinarbasi, E., Akgun, E., Gurlek, F., Cetin, A., 2006. Lack of association between the CYP11B2 gene polymorphism and preeclampsia, eclampsia, and the HELLP syndrome in Turkish women. Eur. J. Obstet. Gynecol. Reprod. Biol. 127, 213–217. https://doi.org/10.1016/j.ejogrb.2005.08.030 Pettit, F., Brown, M.A., 2012. The management of pre-eclampsia: what we think we know. Eur. J. Obstet. Gynecol. Reprod. Biol. 160, 6–12. https://doi.org/10.1016/j.ejogrb.2011.09.049 Ramirez-Salazar, M., Romero-Gutierrez, G., Zaina, S., Malacara, J.M., Kornhauser, C., PerezLuque, E., 2011. Relationship of aldosterone synthase gene (C-344T) and mineralocorticoid receptor (S810L) polymorphisms with gestational hypertension. J. Hum. Hypertens. 25, 320–326. https://doi.org/10.1038/jhh.2010.58 Savelieva, G.M., Efimov, V.S., Grishin, V.L., Shalina, R.I., Kashezheva, A.Z., 1995. Blood coagulation changes in pregnant women at risk of developing preeclampsia. Int. J. Gynaecol. Obstet. 48, 3–8. Shojaati, K., Causevic, M., Kadereit, B., Dick, B., Imobersteg, J., Schneider, H., Beinder, E., Kashiwagi, M., Frey, B.M., Frey, F.J., Mohaupt, M.G., 2004. Evidence for compromised aldosterone synthase enzyme activity in preeclampsia. Kidney Int. 66, 2322–2328. https://doi.org/10.1111/j.1523-1755.2004.66031.x Sibai, B., Dekker, G., Kupferminc, M., 2005. Pre-eclampsia. Lancet (London, England) 365, 785–799. https://doi.org/10.1016/S0140-6736(05)17987-2 Southan, G.J., Szabo, C., 1996. Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem. Pharmacol. 51, 383–394.
Tranquilli, A.L., Landi, B., Giannubilo, S.R., Sibai, B.M., 2012. Preeclampsia: No longer solely a pregnancy disease. Pregnancy Hypertens. 2, 350–357. https://doi.org/10.1016/j.preghy.2012.05.006 Tripodi, G., Valtorta, F., Torielli, L., Chieregatti, E., Salardi, S., Trusolino, L., Menegon, A., Ferrari, P., Marchisio, P.C., Bianchi, G., 1996. Hypertension-associated point mutations in SNP
ADD1 c.1378G>T AGTR2 c.1675G>A AGTR1 c.1166 A>C NOS3 c.+894 G>T CYP11B2 c.-344C>T
Genotypes
Control, n (%)
Case, n (%)
OR( 95% CI )
G/G G/T T/T G/G G/A A/A A/A A/C C/C G/G G/T T/T C/C C/T T/T
85(82.5%) 14(13.6%) 4(3.9%) 35(33.9%) 46 (44.7%) 22(21.4%) 78(75.7%) 22(21.4%) 3(2.9%) 62(60.2%) 38(36.9%) 3(2.9%) 28 (27.2%) 54(52.4%) 21(20.4%)
87(74.3%) 18(15.5%) 12(10.2%) 13(11.1%) 62(53%) 42(35.9%) 77(65.8%) 38(32.5%) 2(1.7%) 79(67.6%) 36(30.7%) 2(1.7%) 26 (22.3%) 76 (64.9%) 15 (12.8%)
1 2.08(0.88-4.94) 2.54(0.44-14.64) 1 1.06(0.45-2.50) 1.36(0.51-3.61) 1 1.62(0.70-3.71) 0.00(0.00-NA) 1 0.65(0.30-1.40) 0.28(0.03-2.78) 1 0.71 (0.28-1.79) 0.23 (0.07-0.74)
p value 0.17 0.81 0.064 0.31 0.025
the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J. Clin. Invest. 97, 2815–2822. https://doi.org/10.1172/JCI118737 Tsukada, K., Ishimitsu, T., Teranishi, M., Saitoh, M., Yoshii, M., Inada, H., Ohta, S., Akashi, M., Minami, J., Ono, H., Ohrui, M., Matsuoka, H., 2002. Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension. J. Hum. Hypertens. 16, 789–793. https://doi.org/10.1038/sj.jhh.1001484 Wang, X.L., Sim, A.S., Badenhop, R.F., McCredie, R.M., Wilcken, D.E., 1996. A smokingdependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat. Med. 2, 41–45. White, P.C., Slutsker, L., 1995. Haplotype analysis of CYP11B2. Endocr. Res. 21, 437–442. Xia, Y., Kellems, R.E., 2009. Is preeclampsia an autoimmune disease? Clin. Immunol. 133, 1– 12. https://doi.org/10.1016/j.clim.2009.05.004
Table 1 Genotype frequencies of each polymorphism in the case and control groups
Table 2 Allele frequencies of each polymorphism in the case and control groups SNP
ADD1 c.1378G>T AGTR2 c.1675G>A AGTR1 c.1166A>C NOS3 c.+894G>T CYP11B2 c.-344C>T
Alleles G T G A A C G T C T
Control, n (%) 184(89.4%) 22(10.6%) 116(56.4%) 90(43.6%) 178(86.4%) 28(13.6%) 162(78.6%) 44(21.4%) 110(53.3%) 96(46.7%)
Case, n (%) 192(82%) 42(18%) 88(37.6%) 146(62.4%) 192(82%) 42 (18%) 194(83%) 40(17%) 128(54.7%) 106(45.3%)
Preeclampsia, polymorphism, CYP11B2, NOS3, ADD1, AGTR1, AGTR2
Mohsen Aziminezhad: Sample Preparation, Data analysis Atieh Teimoori Laboratory Technician Reza Ebrahimzadeh Data analysis, submission, writing the article
Confl icts of Interest Statement Manuscript title: Association of CYP11B2 gene polymorphism with Preeclampsia in north east of Iran (Khorasan province) Author names: Mohsen Azimi-Nezhad, 11/December/2019 Atieh Teymoori 11/December/2019 Reza Ebrahimzadeh-Vesal 11/December/2019
All authors declare no conflict of interests. Corresponding author: Reza Ebrahimzadeh-Vesal
Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. [email protected] [email protected]
Research Highlight
Preeclampsia (PE) is one of the major causes of fetal and maternal mortality. PE is a multifactorial disorder with an unknown cause yet. There is a significant association between CYP11B2 -344C>T gene polymorphism with PE.
S0378-1119(20)30027-5 https://doi.org/10.1016/j.gene.2020.144358 GENE 144358
To appear in:
Gene Gene
Received Date: Revised Date: Accepted Date:
20 June 2019 7 January 2020 8 January 2020
Please cite this article as: M. Azimi-Nezhad, A. Teymoori, R. Ebrahimzadeh-Vesal, Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province), Gene Gene (2020), doi: https://doi.org/ 10.1016/j.gene.2020.144358
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier B.V.
Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province)
Mohsen Azimi-Nezhad1, Atieh Teymoori2, Reza Ebrahimzadeh-Vesal3,4*
1. Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2- Department of Medical Genetics, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. 3- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. Electronic address: [email protected]. 4-Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, IRAN.
Association of CYP11B2 Gene Polymorphism with Preeclampsia in North East of Iran (Khorasan province)
Mohsen Azimi-Nezhad1, Atieh Teymoori2, Reza Ebrahimzadeh-Vesal3,4*
1. Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2- Department of Medical Genetics, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. 3- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. Electronic address: [email protected]. 4-Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, IRAN. * Corresponding author: Reza Ebrahimzadeh-Vesal
Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. [email protected] [email protected]
Abstract Abstract Purpose: Identification the genetic factors in preeclampsia (PE) are useful to increase the current knowledge of the pathophysiology of the disorder. The genetic factors implicated for all cases of PE remain to be determined. This study was aimed to investigate association between ADD1 1378G>T, AGTR2 1675G>A, AGTR1 1166A>C, NOS3 894 G>T and CYP11B2 -344C>T gene polymorphisms in Iranian women with PE.
Material and Methods: 117 pregnant women with PE and 103 healthy women without affected previous pregnancy by PE were selected. Genomic DNA was extracted from peripheral blood and realtime PCR was performed to investigate the polymorphisms using a commercial kit.
Results: There was a significant difference in CYP11B2 -344C>T gene polymorphism between case and control groups (P=0.025). The odds ratio was 0.71 (CI 95% = 0.28-1.79). There were no statistical significant differences between other genetic polymorphisms.
Conclusion: Our results showed a significant association between CYP11B2 -344C>T gene polymorphism with PE. This finding suggests that mentioned polymorphism may be associated with susceptibility to PE at least in IRAN.
Keywords: Preeclampsia, polymorphism, CYP11B2, NOS3, ADD1, AGTR1, AGTR2
1. Introduction Preeclampsia is one of the most common complications of pregnancy which characterized by proteinuria and high blood pressure in second half of pregnancy. It is one of the main causes of maternal and fetal morbidity and mortality. Its prevalence is about 5-8% of all pregnancies worldwide. Usually and about 20-25% of women with a history of chronic hypertension develop PE (Hutcheon et al., 2011; Mohaupt, 2007; Pettit and Brown, 2012; Sibai et al., 2005; Tranquilli et al., 2012; Xia and Kellems, 2009). HELLP syndrome is a severe form of pregnancy complication characterized by hemolysis (H), elevated liver enzymes (EL) and low platelets (LP). This syndrome has a significant contribution to maternal and fetal mortality (Eiland et al., 2012; Mohaupt, 2007; Mutter and Karumanchi, 2008). Unfortunately, there is currently no definitive treatment for women with PE. Prevention of PE is controversial and a health care control during pregnancy is recommended for the prevention of this disorder. The exact cause of the disorder is still unknown. Several studies suggest that immunologic factors, coagulation disorders, nutritional factors, and also reactive oxygen radicals can develop PE (Broughton Pipkin and Rubin, 1994; Chaouat et al., 2003; Hung and Burton, 2006; Maine, 2000; Savelieva et .al., 1995) Preeclampsia has no clear mode of inheritance and different genetic variants are associated with susceptibility to this disorder. However, PE is a complex genetic disorder and the main genetic .causes of PE has not been elucidated yet (Bernard and Giguere, 2003) Alpha adducin (ADD1) is one of the candidate gene for essential hypertension(Casari et al., 1995; Matsuoka et al., 2000; Tripodi et al., 1996). Epidemiological studies have been shown association of ADD1 1378G>T polymorphism with hypertension in different populations (Iwai et al., 1997; Kamitani et al., 1998; Manunta et al., 1998).
Angiotensinogen protein is an important part of the Renin–angiotensin (RA) system which encoded by angiotensin gene (AGT). Renin-angiotensin Aldosterone system, RAAS, is the most important system for regulation of salt metabolism and control of blood pressure. It has been suggested that several single nucleotide polymorphisms in associated genes with RA system, may has an important role in the regulation of hypertension and pathogenicity of PE (Choi et al., 2004). Nitric oxide synthase 3 (NOS3) is located on the long arm of chromosome 7 and its protein has a function in the regulation of blood pressure(Southan and Szabo, 1996). Previous studies showed association of NOS3 -894G>T (rs1799983) polymorphism with blood pressure (Hingorani et al., 1999; Wang et al., 1996). The CYP11B2 gene is located on the long arm of chromosome 8 and provides instructions for making an enzyme called aldosterone synthase (Shojaati et al., 2004; White and Slutsker, 1995). Previous studies showed that -344T/C polymorphism in the promoter region of human CYP11B2 gene is associated with genetic predisposition to hypertension (Tsukada et al., 2002). The overall prevalence of PE in Iranian population is about 5%. In this study we examined the association of ADD1 1378G>T (rs4961), AGTR2 1675G>A (rs1403543), AGTR1 1166 A>C (rs5186), NOS3 +894 G>T (rs1799983) and CYP11B2 -344C>T (rs1799998) gene polymorphisms with PE in a population of Iranian women. 2. Material and Methods 2.1. Sample preparation This case-control study was performed on 117 women with a diagnosis of PE (blood pressure>140/90 mmHg and proteinuria> 0.3 g in 24 hours urine samples after 20 weeks of pregnancy) in the case group and 103 normotensive women with at least one normal pregnancy without history of PE in the control group. The mean age of case samples was 28.5 years (From 20 to 37 ages) and all of the cases samples had singleton pregnancy. The women in case and control groups were normotensive before pregnancy. About 35% of case samples and 25% of control samples had consanguineous marriage. The samples were collected from May 2017 and March 2018 in Neyshabur Hakim hospital in the Razavi Khorasan province. This research has been approved by ethics committee of Neyshabour University of Medical Sciences (IR.NUMS.REC.1396.1). Written consent was obtained from all the participants in the study.
2.2. DNA extraction and genotyping The genomic DNA was extracted from peripheral blood using high pure PCR template preparation kit (Roche) according to the manufacturer's protocol. Genotyping was performed using real-time PCR hypertension SNP kit according to the manufacturer's protocol. (DNATechnology, Russia). All real-time PCR reactions were carried out in duplicate in DT-Prime 4 color real-time PCR thermocycler (DNA-Technology, Russia). Genotypes of SNPs were determined based on simultaneous hybridization of two alternative sequence-specific typing probes labeled with different fluorophores using melting curve analysis according to protocol guideline. 2.3. Statistical Analysis Statistical analysis was performed using the SNP stats online software. The comparison of the allele and genotype frequencies between patient and control groups was performed using chisquare and t-test by the SPSS software (version 19). The p-values less than 0.05 were considered statistically significance.
3. Results The analysis of CYP11B2 -344C>T polymorphism showed a significant differences between homozygous TT (12.8% vs 20.4%) and heterozygous CT genotypes (64.9% vs 52.4%) in the case and control groups, respectively (p value=0.025, OR =0.71, CI 95% = 0.28-1.79) (Table 1). The analysis of ADD1 1378G>T gene polymorphism was not significantly different between homozygous TT (10.2% vs. 3.9%), heterozygous GT (15.5% vs 13.6%) and homozygous GG genotypes (74.3% vs 82.5%) in the case and control groups respectively (Table 1). There were no significant differences in the frequency of ADD1 G (82% vs. 89.4 %) and T alleles (18% vs 10.6%) in both case and control groups (Table 2). Analysis of AGTR2 1675G>A in the case and control groups did not show a significant differences between homozygous AA (35.9% vs 21.4%), heterozygous AG (53% vs 44.7%) and homozygous GG genotypes (11.1% vs 33.9%) (Table1). Frequency of G allele (37.6 % vs 56.4 %) and A allele was (62.4% vs 43.6 %) similar in the case and control groups, respectively (Table 2). The analysis of AGTR1 1166 A>C polymorphism showed no significant differences
between homozygous CC (1.7% vs 2.9%), heterozygous AC (32.5 % vs 21.4%) and homozygous AA (65.8% vs 75.7%) in the case and control groups (Table 1). There was no significance difference in the frequency of A allele (82% vs 86.4%) and C allele (18% vs 13.6%) between both groups (Table 2). The analysis of NOS3 +894 G>T polymorphism showed no significant differences between homozygous TT (1.7% vs 2.9%), heterozygous GT (30.7% vs 36.9%) and homozygous GG (67.6% vs 60.2%) genotypes in both case and control groups (Table 1). Frequency of G allele (83% vs78.6%) and T allele (17% vs. 21.4%) did not show significant differences (Table 2).
4. Discussion Preeclampsia is a complex multifactorial disorder influenced by both genetic and environmental factors. Interaction of multiple genetic and environmental factors is known in the etiology of PE. Hypertension during pregnancy is one of the major causes of PE. Preeclampsia is one of the main causes of maternal and fetal morbidity. Many researchers studied genetic variants with putative effects on PE in different populations. CYP11B2 gene codes for a member of the cytochrome P450 family of enzymes which called aldosterone synthase. Aldosterone is the major mineralocorticoid hormone to regulate of blood pressure in human. Polymorphisms in associated genes in RAAS system may have effects on blood pressure. Hypertension is well known as one of the major components of PE. Previous study showed that -344 C allele binds to SF-1 four times more than the T allele which is associated with increased serum aldosterone level (White and Slutsker, 1995). The -344C>T polymorphism in the promoter region of CYP11B2 gene is a putative binding site for steroidogenic transcription factor1 (SF-1). An alteration on aldosterone synthase gene (CYP11B2) expression may be responsible as one of the causes of hypertension and then predisposition to PE. In the present case-control study, the frequency of heterozygous C/T genotypes in women with PE was statistically higher than the control group. Therefore, this polymorphism may be a risk factor for PE at least in the Iranian population. In another study, in Turkish population, no association between the CYP11B2 gene polymorphism and PE has been reported (Percin et al., 2006). Analysis of 344C>T polymorphism of CYP11B2 gene in women with PE in Caucasian population showed that frequency of TT genotype was significantly higher
in patients than in controls and they concluded that this polymorphism may be associated with developing PE during pregnancy(Bogacz et al., 2016). Analysis of CYP11B2 (C-344T) gene polymorphism in 603 South African Black pregnant women showed that the CT genotype was statistically significant between normotensive and PE groups(Aung et al., 2018). Frequency of 344T/C polymorphism on one hundred Mexican women was similar in the hypertensive and normotensive pregnant women and suggested that genotype of -344T/C of CYP11B2 was neither related with gestational hypertension nor with aldosterone levels at delivery.(Ramirez-Salazar et al., 2011). This lack of reproducibility between our data and other studies somehow may be explained by population diversity. We have detected no association between genotype and allele frequencies of ADD1 1378G>T, AGTR2 1675G>A, AGTR1 1166 A>C and NOS3 894 G>T polymorphisms with PE. These variants need to further studies in different populations to elucidate their putative function to develop of hypertension and PE. 7 Some imitations of this study include the relatively small number of the participants. This may be reduced the power of study to detect associations. Also, discrepancy in allele and genotype frequencies with Hardy– Weinberg equilibrium (HWE) may be explained with consanguineous marriage in some of the case and control samples.
Acknowledgment This study was approved and funded by a grant from Neyshabur University of Medical Sciences. Number of approval was IR.NUMS.REC.1396, thesis code: 203. We also thank participants in this study. Conflict of interest All authors declare no conflict of interests
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ADD1 c.1378G>T AGTR2 c.1675G>A AGTR1 c.1166 A>C NOS3 c.+894 G>T CYP11B2 c.-344C>T
Genotypes
Control, n (%)
Case, n (%)
OR( 95% CI )
G/G G/T T/T G/G G/A A/A A/A A/C C/C G/G G/T T/T C/C C/T T/T
85(82.5%) 14(13.6%) 4(3.9%) 35(33.9%) 46 (44.7%) 22(21.4%) 78(75.7%) 22(21.4%) 3(2.9%) 62(60.2%) 38(36.9%) 3(2.9%) 28 (27.2%) 54(52.4%) 21(20.4%)
87(74.3%) 18(15.5%) 12(10.2%) 13(11.1%) 62(53%) 42(35.9%) 77(65.8%) 38(32.5%) 2(1.7%) 79(67.6%) 36(30.7%) 2(1.7%) 26 (22.3%) 76 (64.9%) 15 (12.8%)
1 2.08(0.88-4.94) 2.54(0.44-14.64) 1 1.06(0.45-2.50) 1.36(0.51-3.61) 1 1.62(0.70-3.71) 0.00(0.00-NA) 1 0.65(0.30-1.40) 0.28(0.03-2.78) 1 0.71 (0.28-1.79) 0.23 (0.07-0.74)
p value 0.17 0.81 0.064 0.31 0.025
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Table 1 Genotype frequencies of each polymorphism in the case and control groups
Table 2 Allele frequencies of each polymorphism in the case and control groups SNP
ADD1 c.1378G>T AGTR2 c.1675G>A AGTR1 c.1166A>C NOS3 c.+894G>T CYP11B2 c.-344C>T
Alleles G T G A A C G T C T
Control, n (%) 184(89.4%) 22(10.6%) 116(56.4%) 90(43.6%) 178(86.4%) 28(13.6%) 162(78.6%) 44(21.4%) 110(53.3%) 96(46.7%)
Case, n (%) 192(82%) 42(18%) 88(37.6%) 146(62.4%) 192(82%) 42 (18%) 194(83%) 40(17%) 128(54.7%) 106(45.3%)
Preeclampsia, polymorphism, CYP11B2, NOS3, ADD1, AGTR1, AGTR2
Mohsen Aziminezhad: Sample Preparation, Data analysis Atieh Teimoori Laboratory Technician Reza Ebrahimzadeh Data analysis, submission, writing the article
Confl icts of Interest Statement Manuscript title: Association of CYP11B2 gene polymorphism with Preeclampsia in north east of Iran (Khorasan province) Author names: Mohsen Azimi-Nezhad, 11/December/2019 Atieh Teymoori 11/December/2019 Reza Ebrahimzadeh-Vesal 11/December/2019
All authors declare no conflict of interests. Corresponding author: Reza Ebrahimzadeh-Vesal
Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran. [email protected] [email protected]
Research Highlight
Preeclampsia (PE) is one of the major causes of fetal and maternal mortality. PE is a multifactorial disorder with an unknown cause yet. There is a significant association between CYP11B2 -344C>T gene polymorphism with PE.