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BMC Medical Genetics

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Open Access 01-12-2019 | Pre-Eclampsia | Research article

MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study

Authors: Feriha Fatima Khidri, Yar Muhammad Waryah, Faiza Kamran Ali, Hina Shaikh, Ikram Din Ujjan, Ali Muhammad Waryah

Published in: BMC Medical Genetics | Issue 1/2019

Abstract

Background

To study the role of single nucleotide variants (SNVs) of genes related to preeclampsia in Pakistani pregnant women.

Methods

After ethical approval and getting informed consent; 250 pregnant women were enrolled and equally divided into two groups (125 preeclamptic cases and 125 normotensive pregnant women). Demographic details and medical history were recorded, and 10 ml blood sample was obtained for DNA extraction. The tetra-primer amplification refractory mutation system (ARMS) assays were developed for assessing the variants of three preeclampsia related genes; F5, MTHFR and VEGFA. An association of six SNVs; F5:c.1601G > A (rs6025), F5:c.6665A > G (rs6027), MTHFR: c.665C > T (rs1801133), MTHFR: c.1286A > C (rs1801131), VEGFA: c.-2055A > C (rs699947) and VEGFA: c.*237C > T (rs3025039) with preeclampsia was determined by using different genetic models.

Results

Genotyping of the SNVs revealed that patients with MTHFR:c.665C > T, have increased susceptibility to preeclampsia (CT versus CC/TT: OR = 2.79, 95% CI = 1.18–6.59; P* = 0.046 and CT/TT vs CC: OR = 2.91, 95% CI = 1.29–6.57; P* = 0.0497, in overdominant and dominant models, respectively), whereas F5:c.6665A > G, (A/G vs AA/GG: OR = 0.42, 95% CI = 0.21–0.84; P* = 0.038 in overdominant model) and MTHFR:c.1286A > C, (CC versus AA: OR = 0.36, 95% CI = 0.18–0.72; P* = 0.0392 in codominant model) have significantly decreased risk for preeclampsia. F5:c.1601G > A, VEGFA: c.-2055A > C and VEGFA: c.*237C > T variants revealed no relationship with the disease.

Conclusion

This is the first case control study describing the protective role of F5:c.6665A > G against preeclampsia in any world population. In addition, the present study confirmed the association and role of MTHFR gene variations in the development of preeclampsia in Pakistani patients. Further genetic studies may be required to better understand the complex genetic mechanism of SNVs in preeclampsia related genes in pregnant women.

Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009;33(3):130–7.CrossRefPubMed

Woolcock J, Hennessy A, Xu B, Thornton C, Tooher J, Makris A, Ogle R. Soluble Flt-1 as a diagnostic marker of pre-eclampsia. Aust N Z J Obstet Gynaecol. 2008;48(1):64–70.CrossRefPubMed

Chappell S, Morgan L. Searching for genetic clues to the causes of pre-eclampsia. Clin Sci. 2006;110(4):443–58.CrossRef

Sánchez-Rodríguez ENN-SS, Mendoza-Rodríguez CA, Romero-Arauz F, Morán C, Cerbón MA. Immune-endocrine alterations during preeclampsia. Open Neuroendocrinol J. 2010;3:143–51.

Roberts JM, Balk JL, Bodnar LM, Belizán JM, Bergel E, Martinez A. Nutrient involvement in preeclampsia. J Nutr. 2003;133(5):1684S–92S.CrossRefPubMed

Williams PJ, Pipkin FB. The genetics of pre-eclampsia and other hypertensive disorders of pregnancy. Best Pract Res Clin Obstetr Gynaecol. 2011;25(4):405–17.CrossRef

Pavlova E, Chemev T, Chemev A, Karagiozova Z. Pregnancy and issues with inherited and acquired thrombophilia. J IMAB-Annula Proc. 2008;1:21–2.

Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum Reprod. 2000;15(8):1830–3.CrossRefPubMed

Pecheniuk N, Morris C, Walsh T, Marsh N. The factor V HR2 haplotype: prevalence and association of the A4070G and A6755G polymorphisms. Blood Coagul Fibrinolysis. 2001;12(3):201–6.CrossRefPubMed

10.

Watanabe H, Hamada H, Yamada N, Sohda S, Yamakawa-Kobayashi K, Yoshikawa H, Arinami T. Association analysis of nine missense polymorphisms in the coagulation factor V gene with severe preeclampsia in pregnant Japanese women. J Hum Genet. 2002;47(3):131–5.CrossRefPubMed

11.

Segers O, Castoldi E. Factor V Leiden and activated protein C resistance. In: Makowski GS, editor. Advances in clinical chemistry. France: Elsevier Masson SAS; 2009;49:121–44.

12.

Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. Role of vascular endothelial growth factor polymorphisms (−2578C> a,-460 T> C,-1154G> a,+ 405G> C and+ 936C> T) in endometriosis: a case–control study with Brazilians. Biomed Central Womens Health. 2014;14(1):117.CrossRef

13.

Al-khuriji AF. The role of vascular endothelial growth factor gene polymorphisms in recurrent spontaneous abortions in Saudi women. J Immunobiol. 2017;2(1):120-23.

14.

Şamlı H, Demir B, Özgöz A, Atalay M, Uncu G. Vascular endothelial growth factor gene 1154 G/a, 2578 C/a, 460 C/T, 936 C/T polymorphisms and association with recurrent pregnancy losses. Genet Mol Res. 2012;11(4):4739–45.CrossRefPubMed

15.

Shaikh N, Waryah AM, Devrajani BR, Rajput MI, Hayat AS, Shaikh S. IL28B rs12980275 polymorphism shows association with response to treatment in Pakistani patients with chronic hepatitis C. J Med Virol. 2015;87(5):814–20.CrossRefPubMed

16.

Shaheen G, Sajid S, Razak S, Mazhar SB, Afsar T, Almajwal A, Alam I, Jahan S. Role of ACE I/D polymorphism in pathological assessment of preeclampsia in Pakistan. Mol Gen Genomic Med. 2019:e799.

17.

ACOG: American college of obstetricians and gynecologists. Hypertension in pregnancy. 2013.

18.

Valensise H, Vasapollo B, Gagliardi G, Novelli GP. Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease. Hypertension. 2008;52(5):873–80.CrossRefPubMed

19.

Salimi S, Saravani M, Yaghmaei M, Fazlali Z, Mokhtari M, Naghavi A, Farajian-Mashhadi F. The early-onset preeclampsia is associated with MTHFR and FVL polymorphisms. Arch Gynecol Obstet. 2015;291(6):1303–12.CrossRefPubMed

20.

Aggarwal S, Dimri N, Tandon I, Agarwal S. Preeclampsia in north Indian women: the contribution of genetic polymorphisms. J Obstet Gynaecol Res. 2011;37(10):1335–41.CrossRefPubMed

21.

Mello G, Parretti E, Marozio L, Pizzi C, Lojacono A, Frusca T, Facchinetti F, Benedetto C. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. Hypertension. 2005;46(6):1270–4.CrossRefPubMed

22.

Waryah AM, Shahzad M, Shaikh H, Sheikh SA, Channa NA, Hufnagel RB, Makhdoom A, Riazuddin S, Ahmed ZM. A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred. Clin Genet. 2016;90(1):90–5.CrossRefPubMed

23.

Ye S, Dhillon S, Ke X, Collins AR, Day IN: An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res 2001, 29(17):E88–88.

24.

Collins A, Ke X. Primer1: primer design web service for tetra-primer ARMS-PCR. Open Bioinformatics J. 2012;6(1):55-58.

25.

Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006.CrossRefPubMedPubMedCentral

26.

Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–9.CrossRefPubMed

27.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.

28.

Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol. 2000;96(1):45–9.PubMed

29.

Venselaar H, te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 2010;11(1):548.CrossRefPubMedPubMedCentral

30.

Sivadas A, Scaria V. Pharmacogenomic survey of Qatari populations using whole-genome and exome sequences. Pharmacogenomics J. 2018;18(4):590.CrossRefPubMed

31.

Wang X, Bai T, Liu S, Pan H, Wang B. Association between thrombophilia gene polymorphisms and preeclampsia: a meta-analysis. PLoS One. 2014;9(6):e100789.CrossRefPubMedPubMedCentral

32.

Yalinkaya A, Erdemoglu M, Akdeniz N, Kale A, Kale E. The relationship between thrombophilic mutations and preeclampsia: a prospective case-control study. Ann Saudi Med. 2006;26(2):105–9.CrossRefPubMedPubMedCentral

33.

Malek-Khosravi S, Rahimi Z, Jalilvand F, Parsian A. Thrombophilic mutations and susceptibility to preeclampsia in Western Iran. J Thromb Thrombolysis. 2012;33(1):109–15.CrossRefPubMed

34.

Yang YL, Yang HL, SPK S. Meta-Prediction of MTHFR Gene Polymorphisms and Air Pollution on the Risk of Hypertensive Disorders in Pregnancy Worldwide. Int J Environ Res Public Health. 2018;15(2):326.

35.

Wang X-m, Wu H-y, X-j Q. Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and risk of preeclampsia: an updated meta-analysis based on 51 studies. Arch Med Res. 2013;44(3):159–68.CrossRefPubMed

36.

Poursadegh Zonouzi A, Chaparzadeh N, Asghari Estiar M, Mehrzad Sadaghiani M, Farzadi L, Ghasemzadeh A, Sakhinia M, Sakhinia E. Methylenetetrahydrofolate reductase C677T and A1298C mutations in women with recurrent spontaneous abortions in the northwest of Iran. ISRN Obstet Gynecol. 2012;2012:945486.PubMedPubMedCentral

37.

Zhang Y, He X, Xiong X, Chuan J, Zhong L, Chen G, Yu D. The association between maternal methylenetetrahydrofolate reductase C677T and A1298C polymorphism and birth defects and adverse pregnancy outcomes. Prenat Diagn. 2019;39(1):3–9.CrossRefPubMed

38.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248.CrossRefPubMedPubMedCentral

39.

Kaiser T, Brennecke SP, Moses EK. Methylenetetrahydrofolate reductase polymorphisms are not a risk factor for pre-eclampsia/eclampsia in Australian women. Gynecol Obstet Investig. 2000;50(2):100–2.CrossRef

40.

Zusterzeel PL, Visser W, Bolm HJ, Peters WH, Heil SG, Steegers EA, Steegers E. Methylenetetrahydrofolate reductase polymorphisms in preeclampsia and the HELLP syndrome. Hypertens Pregnancy. 2000;19(3):299–307.CrossRefPubMed

41.

Davalos I, Moran M, Martinez-Abundis E, Gonzalez-Ortiz M, Flores-Martinez S, Machorro V, Sandoval L, Figuera L, Mena J, Oliva J. Methylenetetrahydrofolate reductase C677T polymorphism and factor V Leiden variant in Mexican women with preeclampsia/eclampsia. Blood Cell Mol Dis. 2005;35(1):66–9.CrossRef

42.

Cheng D, Hao Y, Zhou W, Ma Y. Vascular endothelial growth factor+ 936C/T,–634G/C,–2578C/a, and–1154G/a polymorphisms with risk of preeclampsia: a meta-analysis. PLoS One. 2013;8(11):e78173.CrossRefPubMedPubMedCentral

43.

Sandrim VC, Palei AC, Cavalli RC, Araujo FM, Ramos ES, Duarte G, Tanus-Santos JE. Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension. Mol Hum Reprod. 2009;15(2):115–20.CrossRefPubMed

44.

Banyasz I, Szabo S, Bokodi G, Vannay A, Vasarhelyi B, Szabo A, Tulassay T, Rigo J Jr. Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia. Mol Hum Reprod. 2006;12(4):233–6.CrossRefPubMed

45.

Shim JY, Jun JK, Jung BK, Kim SH, Won HS, Lee PR, Kim A. Vascular endothelial growth factor gene +936 C/T polymorphism is associated with preeclampsia in Korean women. Am J Obstetr Gynecol. 2007;197(3):271 e271–4.CrossRef

46.

Morrison ER, Miedzybrodzka ZH, Campbell DM, Haites NE, Wilson B, Watson M, Greaves M, Vickers MA. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost. 2002;87(05):779–85.CrossRefPubMed

47.

Papazoglou D, Galazios G, Koukourakis MI, Kontomanolis EN, Maltezos E. Association of -634G/C and 936C/T polymorphisms of the vascular endothelial growth factor with spontaneous preterm delivery. Acta Obstet Gynecol Scand. 2004;83(5):461–5.PubMed

48.

Chedraui P, Solis EJ, Bocci G, Gopal S, Russo E, Escobar GS, Hidalgo L, Pérez-López FR, Genazzani AR, Mannella P. Feto-placental nitric oxide, asymmetric dimethylarginine and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. J Matern Fetal Neonatal Med. 2013;26(3):226–32.CrossRefPubMed

49.

Andraweera PH, Dekker GA, Dissanayake VH, Bianco-Miotto T, Jayasekara RW, Roberts CT. Vascular endothelial growth factor family gene polymorphisms in preeclampsia in Sinhalese women in Sri-Lanka. J Matern Fetal Neonatal Med. 2013;26(5):532–6.CrossRefPubMed

50.

Garza-Veloz I, Castruita-De la Rosa C, Cortes-Flores R, Martinez-Gaytan V, Rivera-Munoz JE, Garcia-Mayorga EA, Meza-Lamas E, Rojas-Martinez A, Ortiz-Lopez R, Martinez-Fierro ML. No association between polymorphisms/haplotypes of the vascular endothelial growth factor gene and preeclampsia. BMC Pregnancy Childbirth. 2011;11:35.CrossRefPubMedPubMedCentral

51.

Kim YJ, Park BH, Park H, Jung SC, Pang MG, Ryu HM, Lee KS, Eom SM, Park HY. No association of the genetic polymorphisms of endothelial nitric oxide synthase, dimethylarginine dimethylaminohydrolase, and vascular endothelial growth factor with preeclampsia in Korean populations. Twin Res Hum Genet. 2008;11(1):77–83.CrossRefPubMed

52.

Qamar R, Ayub Q, Mohyuddin A, Helgason A, Mazhar K, Mansoor A, Zerjal T, Tyler-Smith C, Mehdi SQ. Y-chromosomal DNA variation in Pakistan. Am J Hum Genet. 2002;70(5):1107–24.CrossRefPubMedPubMedCentral

53.

Das R, Upadhyai P. Investigating the west Eurasian ancestry of Pakistani Hazaras. J Genet. 2019;98(2):43.CrossRefPubMed

54.

Bhatti S, Abbas S, Aslamkhan M, Attimonelli M, Trinidad MS, Aydin HH, de Souza EMS, Gonzalez GR. Genetic perspective of uniparental mitochondrial DNA landscape on the Punjabi population, Pakistan. Mitochondrial DNA Part A. 2018;29(5):714–26.CrossRef

55.

Yasmin M, Rakha A, Noreen S, Salahuddin Z. Mitochondrial control region diversity in Sindhi ethnic group of Pakistan. Legal Med. 2017;26:11–3.CrossRefPubMed

56.

Afsar NA, Bruckmueller H, Werk AN, Nisar MK, Ahmad H, Cascorbi I. Implications of genetic variation of common drug metabolizing enzymes and ABC transporters among the Pakistani population. Sci Rep. 2019;9(1):7323.CrossRefPubMedPubMedCentral

57.

Idrees R, Fatima S, Abdul-Ghafar J, Raheem A, Ahmad Z. Cancer prevalence in Pakistan: meta-analysis of various published studies to determine variation in cancer figures resulting from marked population heterogeneity in different parts of the country. World J Surg Oncol. 2018;16(1):129.CrossRefPubMedPubMedCentral

58.

Ullah S, Aslamkhan M, Rasheed A. Molecular distribution of deafness loci in various ethnic groups of the Punjab, Pakistan. J Coll Physicians Surg Pak. 2015;25(8):573–8.PubMed

59.

Saraswathy KN, Asghar M, Samtani R, Murry B, Mondal PR, Ghosh PK, Sachdeva MP. Spectrum of MTHFR gene SNPs C677T and A1298C: a study among 23 population groups of India. Mol Biol Rep. 2012;39(4):5025–31.CrossRefPubMed

60.

Mitriuc D, Popuşoi O, Catrinici R, Friptu V. The obstetric complications in women with hereditary thrombophilia. Med Pharm Rep. 2019;92(2):106.PubMedPubMedCentral

61.

Bodnar LM, Catov JM, Klebanoff MA, Ness RB, Roberts JM. Prepregnancy body mass index and the occurrence of severe hypertensive disorders of pregnancy. Epidemiology. 2007;18(2):234–9.CrossRefPubMed

62.

Neuman M, Kawachi I, Gortmaker S, Subramanian S. Urban-rural differences in BMI in low-and middle-income countries: the role of socioeconomic status. Am J Clin Nutr. 2013;97(2):428–36.CrossRefPubMedPubMedCentral

63.

van Middendorp D, ten Asbroek A, Bio FY, Edusei A, Meijjer L, Newton S, Agyemang C. Rural and urban differences in blood pressure and pregnancy-induced hypertension among pregnant women in Ghana. Glob Health. 2013;9:59.CrossRef

64.

Shamsi U, Hatcher J, Shamsi A, Zuberi N, Qadri Z, Saleem S. A multicentre matched case control study of risk factors for preeclampsia in healthy women in Pakistan. BMC Womens Health. 2010;10(1):14.CrossRefPubMedPubMedCentral

65.

Cnossen J, Leeflang M, De Haan E, Mol B, Van der Post J, Khan K, Ter Riet G. Systematic review: accuracy of body mass index in predicting pre-eclampsia: bivariate meta-analysis. BJOG Int J Obstet Gynaecol. 2007;114(12):1477–85.CrossRef

Title: MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study
Authors: Feriha Fatima Khidri
Yar Muhammad Waryah
Faiza Kamran Ali
Hina Shaikh
Ikram Din Ujjan
Ali Muhammad Waryah
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Pre-Eclampsia
Published in: BMC Medical Genetics / Issue 1/2019
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-019-0905-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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