Association of EPHX1 Gene Polymorphisms (rs1051740 and rs2234922) with Preeclampsia among Pregnant Women in Lagos, Nigeria: A Molecular Case-Control Study
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Abstract
Background: Preeclampsia (PE) remains a contributor to maternal and foetal morbidity and mortality, especially in resource-limited regions. Genetic predisposition may influence susceptibility, with the EPHX1 gene, central to xenobiotic metabolism and oxidative stress, implicated through two missense single nucleotide polymorphisms (SNPs), rs1051740 and rs2234922. Study determined the association between EPHX1 SNPs and preeclampsia risk, evaluating allele frequencies and clinical correlations.
Methodology: A case-control study conducted among 200 pregnant women (97 with PE and 103 controls) across three maternity hospitals in Lagos State. Ethical approvals and informed consent were obtained. Data on socio-demographic, lifestyle, and maternal clinical parameters were collected using structured questionnaires. Blood samples were collected for EPHX1 SNPs genotyped using PCR-based method. Descriptive statistics, chi-square and Fisher’s exact tests, t-tests, correlation, and linear regression were conducted with p < 0.05.
Results: The mean age of women with preeclampsia was higher than that of normotensive women but no significant age difference was observed between the two groups (PE: 31.93 ± 4.91; Controls: 30.55 ± 5.73; p = 0.071). Body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and proteinuria were all significantly elevated in the preeclamptic group compared to controls (p < 0.0001). The rs1051740 C allele (mutant, minor) was significantly more frequent and associated with PE cases (49.5%) than controls (15.8%) (p = 7.4 × 10-7), showing a positive correlation with SBP (r = 0.222, p = 0.030). While the rs2234922 A allele (wild-type, major) was also significantly associated with PE (p = 0.00784), it did not exhibit a statistically significant correlation with SBP. Both alleles confer PE risk.
Conclusion: Findings highlight a significant association between EPHX1 SNPs and preeclampsia, emphasising the role of genetic predisposition within the multifactorial context of disease risk in this population
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References
1. Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ (Online). 2019;366:l2381. doi:10.1136/bmj.l2381
2. Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstetrics and gynecology (New York 1953). 2020;135(6):e237-e260. doi: 10.1097/AOG.0000000000003891
3. Homer CS, Brown MA, Mangos G, Davis GK. Non-proteinuric pre-eclampsia: a novel risk indicator in women with gestational hypertension. Journal of hypertension. 2008;26(2):295-302. doi: 10.1097/HJH.0b013e3282f1a953
4. National Institute for Health and Care Excellence (NICE). Hypertension in pregnancy: diagnosis and management. NICE guideline NG133. London: NICE; 2019.
5. Özgen G, Dincgez Cakmak B, Özgen L, Uguz S, Sager H. The role of oligohydramnios and fetal growth restriction in adverse pregnancy outcomes in preeclamptic patients. Ginekologia polska. 2022;93(3):235-241. doi:10.5603/GP.a2021.0094
6. Torres-Torres J, Espino-y-Sosa S, Martinez-Portilla R, Borboa-Olivares H, Estrada-Gutierrez G, Acevedo-Gallegos S, et al. A Narrative Review on the Pathophysiology of Preeclampsia. International journal of molecular sciences. 2024;25(14):7569. doi:10.3390/ijms25147569
7. World Health Organization (WHO). Pre‑eclampsia. Geneva: WHO; 2025.
8. World Health Organization. The World Health Report 2005: Make every mother and child count. Geneva: World Health Organization; 2005.
9. Zhang N, Tan J, Yang H, Khalil RA. Comparative risks and predictors of preeclamptic pregnancy in the Eastern, Western and developing world. Biochemical pharmacology. 2020;182. doi:10.1016/j.bcp.2020.114247
10. Kokori E, Aderinto N, Olatunji G, Komolafe R, Babalola EA, Isarinde DT, et al. Prevalence and materno-fetal outcomes of preeclampsia/eclampsia among pregnant women in Nigeria: a systematic review and meta-analysis. European journal of medical research. 2024;29(1). doi:10.1186/s40001-024-02086-x
11. Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia-Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2020;76(14):1690. doi:10.1016/j.jacc.2020.08.014
12. Laine K, Murzakanova G, Sole KB, Pay AD, Heradstveit S, Räisänen S. Prevalence and risk of pre-eclampsia and gestational hypertension in twin pregnancies: a population-based register study. BMJ open. 2019;9(7):e029908. doi:10.1136/bmjopen-2019-029908
13. Meazaw MW, Chojenta C, Muluneh MD, Loxton D. Systematic and meta-analysis of factors associated with preeclampsia and eclampsia in sub-Saharan Africa. PloS one. 2020;15(8):e0237600. doi:10.1371/journal.pone.0237600
14. Staff AC. The two-stage placental model of preeclampsia: An update. Journal of reproductive immunology. 2019;134-135:1-10. doi:10.1016/j.jri.2019.07.004
15. Roberts JM, Rich-Edwards JW, McElrath TF, Garmire L, Myatt L. Subtypes of Preeclampsia: Recognition and Determining Clinical Usefulness. Hypertension (Dallas, Tex 1979). 2021;77(5):1430-1441. doi:10.1161/HYPERTENSIONAHA.120.14781
16. Dimitriadis E, Rolnik DL, Zhou W, Estrada-Gutierrez G, Koga K, Francisco RP.V., et al. Pre-eclampsia. Nature reviews Disease primers. 2023;9(1). doi:10.1038/s41572-023-00417-6
17. Phoswa WN, Khaliq OP. The Role of Oxidative Stress in Hypertensive Disorders of Pregnancy (Preeclampsia, Gestational Hypertension) and Metabolic Disorder of Pregnancy (Gestational Diabetes Mellitus). Jakovljevic V, ed. Oxidative medicine and cellular longevity. 2021;2021(1):5581570. doi:10.1155/2021/5581570
18. Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. International journal of gynecology and obstetrics. 1998;60(1):23-27. doi:10.1016/S0020-7292(97)00241-5
19. Mütze S, Rudnik-Schöneborn S, Zerres K, Rath W. Genes and the preeclampsia syndrome. Journal of perinatal medicine. 2008;36(1):38-58. doi:10.1515/JPM.2008.004
20. Valenzuela FJ, Pérez-Sepúlveda A, Torres MJ, Correa P, Repetto GM, E. Illanes S. Pathogenesis of Preeclampsia: The Genetic Component. Iavazzo C, ed. Journal of Pregnancy. 2012;2012(2012):279-286. doi:10.1155/2012/632732
21. Yong HEJ, Murthi P, Brennecke SP, Moses EK. Genetic Approaches in Preeclampsia. In: Vaillancourt C, Murthi P, eds. Preeclampsia. Springer New York; 2018:53-72. doi:10.1007/978-1-4939-7498-6_5
22. Ward K, Laivuori H, Taylor RN. Genetic Factors in the Etiology of Preeclampsia/Eclampsia. In: Taylor RN, ed. Chesley’s Hypertensive Disorders in Pregnancy. Fifth Edition. Elsevier Science & Technology; 2022:45-69. doi:10.1016/B978-0-12-818417-2.00002-6
23. CHESLEY LC, ANNITTO JE, COSGROVE RA. The Familial Factor in Toxemia of Pregnancy. Obstetrics and gynecology (New York 1953). 1968;32(3):303-311.
24. Thornton JG, Macdonald AM. Twin mothers, pregnancy hypertension and pre‐eclampsia. BJOG: an international journal of obstetrics and gynaecology. 1999;106(6):570-575. doi:10.1111/j.1471-0528.1999.tb08326.x
25. O’Shaughnessy KM, Ferraro F, Fu B, Downing S, Morris NH. Identification of monozygotic twins that are concordant for preeclampsia. American journal of obstetrics and gynecology. 2000;182(5):1156-1157. doi:10.1067/mob.2000.105429
26. Haig D. Genetic Conflicts in Human Pregnancy. The Quarterly review of biology. 1993;68(4):495-532. doi:10.1086/418300
27. Morales J, Welter D, Bowler EH, Cerezo M, Harris LW, McMahon AC, et al. A standardized framework for representation of ancestry data in genomics studies, with application to the NHGRI-EBI GWAS Catalog. Genome Biology. 2018;19(1). doi:10.1186/s13059-018-1396-2
28. Zusterzeel PLM, Peters WHM, Visser W, Hermsen KJM, Roelofs HMJ, Steegers EAP. A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia. Journal of medical genetics. 2001;38(4):234-237. doi:10.1136/jmg.38.4.234
29. Laasanen J, Romppanen EL, Hiltunen M, Helisalmi S, Mannermaa A, Punnonen K, et al. Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. European journal of human genetics : EJHG. 2002;10(9):569-573. doi:10.1038/sj.ejhg.5200849
30. Zhu Q shi, Xing W, Qian B, von DP, Shneider BL, Fox VL, et al. Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia. Biochimica et biophysica acta Molecular basis of disease. 2003;1638(3):208-216. doi:10.1016/S0925-4439(03)00085-1
31. Buehler BA, Delimont D, van Waes M, Finnell RH. Prenatal Prediction of Risk of the Fetal Hydantoin Syndrome. The New England journal of medicine. 1990;322(22):1567-1572. doi:10.1056/NEJM199005313222204
32. Hassett C, Robinson KB, Beck NB, Omiecinski CJ. The Human Microsomal Epoxide Hydrolase Gene (EPHX1): Complete Nucleotide Sequence and Structural Characterization. Genomics (San Diego, Calif). 1994;23(2):433-442. doi:10.1006/geno.1994.1520
33. Nguyen HL, Yang X, Omiecinski CJ. Expression of a novel mRNA transcript for human microsomal epoxide hydrolase (EPHX1) is regulated by short open reading frames within its 5′-untranslated region. RNA (Cambridge). 2013;19(6):752-766. doi:10.1261/rna.037036.112
34. Hassett C, Aicher L, Sidhu JS, Omiecinski CJ. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Human molecular genetics. 1994;3(3):421-428. doi:10.1093/hmg/3.3.421
35. Politi C, Roumeliotis S, Tripepi G, Spoto B. Sample Size Calculation in Genetic Association Studies: A Practical Approach. Life (Basel, Switzerland). 2023;13(1):235. doi:10.3390/life13010235
36. Ioannidis JPA. Genetic associations: false or true? Trends in molecular medicine. 2003;9(4):135-138. doi:10.1016/S1471-4914(03)00030-3
37. Fagbayi TA, Somade AO, Adefemi AK and Shonde OG. Association of angiotensinogen rs699 single nucleotide polymorphism and pre-eclampsia in Lagos, Nigeria: A case-control study. Ife Journal of Science. doi:10.4314/ijs.v26i2.16
38. Kamal MA, Ali Elsaadany Z, Bahaa Fouad N, Elaal AAA, Makhlouf MM, Shabaan MM, et al. Genetic Polymorphism of Microsomal Epoxide Hydrolase Enzyme Gene in Preeclamptic Females. The American journal of the medical sciences. 2012;343(4):291-294. doi:10.1097/MAJ.0b013e31822be635
39. Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC bioinformatics. 2012;13(1). doi:10.1186/1471-2105-13-134
40. Tessema KF, Gebremeskel F, Getahun F, Chufamo N, Misker D. Individual and Obstetric Risk Factors of Preeclampsia among Singleton Pregnancy in Hospitals of Southern Ethiopia. Katsuya T, ed. International journal of hypertension. 2021;2021:1-8. doi:10.1155/2021/7430827
41. Lin L, Huai J, Su R, Wang C, Li B, Yang H. Incidence and Clinical Risk Factors for Preeclampsia and Its Subtypes: A Population-Based Study in Beijing, China. Maternal-fetal medicine (Online). 2021;3(2):91-99. doi:10.1097/FM9.0000000000000099
42. Kassa BG, Asnkew S, Ayele AD, Nigussie AA, Demilew BC, Mihirete GN. Preeclampsia and its determinants in Ethiopia: A systematic review and meta-analysis. PloS one. 2023;18(11):e0287038. doi:10.1371/journal.pone.0287038
43. Haile TG, Assefa N, Alemayehu T, Mariye T, Geberemeskel GG, Bahrey D, et al. Determinants of Preeclampsia among Women Attending Delivery Services in Public Hospitals of Central Tigray, Northern Ethiopia: A Case-Control Study. Scioscia M, ed. Journal of pregnancy. 2021;2021:1-8. doi:10.1155/2021/4654828
44. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005;330(7491):565-567. doi:10.1136/bmj.38380.674340.E0
45. Facchinetti F, Allais G, D’Amico R, Benedetto C, Volpe A. The relationship between headache and preeclampsia: a case–control study. European journal of obstetrics & gynecology and reproductive biology. 2005;121(2):143-148. doi:10.1016/j.ejogrb.2004.12.020
46. LYKKE JA, BARE LA, OLSEN J, LAGIER R, TONG C, ARELLANO A, et al. Vascular associated gene variants in patients with preeclampsia: results from the Danish National Birth Cohort. Acta obstetricia et gynecologica Scandinavica. 2012;91(9):1053-1060. doi:10.1111/j.1600-0412.2012.01479.x
47. Groten T, Schleussner E, Lehmann T, Reister F, Holzer B, Danso KA, et al. eNOSI4 and EPHX1 polymorphisms affect maternal susceptibility to preeclampsia: analysis of five polymorphisms predisposing to cardiovascular disease in 279 Caucasian and 241 African women. Archives of gynecology and obstetrics. 2014;289(3):581-593. doi:10.1007/s00404-013-2991-9
48. Aljuaid N, Muharram E, Loqtum N, Al-Amoudi R, AlMahdi H, Salama M, et al. Association of four missense SNPs with preeclampsia in Saudi women. Saudi journal of medicine and medical sciences. 2020;8(3):174-180. oi:10.4103/sjmms.sjmms_280_19