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Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 5/2019

01-05-2019 | Miscarriage | Genetics

The role of FAS, FAS-L, BAX, and BCL-2 gene polymorphisms in determining susceptibility to unexplained recurrent pregnancy loss

Authors: Rafael Tomoya Michita, Francis Maria Báo Zambra, Lucas Rosa Fraga, Maria Teresa Sanseverino, Lavínia Schuler-Faccini, José Artur Bogo Chies, Priscila Vianna

Published in: Journal of Assisted Reproduction and Genetics | Issue 5/2019

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Abstract

Purpose

Idiopathic recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder where an impaired control of apoptosis is likely involved. Triggering the cell death mechanism occurs in a spatiotemporal manner and is strongly related to a healthy pregnancy. Single nucleotide polymorphisms (SNPs) at the regulatory regions of genes are known to influence the expression patterns of apoptosis-related molecules.

Methods

A total of 296 unrelated female Brazilian patients were evaluated for clinical-demographic variables and genetic factors: 140 women who had experienced an unexplained RPL (with at least two consecutive abortions) and 156 healthy multiparous women. In all patients, six SNPs were evaluated in genes of apoptosis-related pathways: FAS (rs2234767, rs1800682), FAS-L (rs763110, rs5030772), BAX (rs4645878), and BCL-2 (rs2279115) by PCR followed by a restriction fragment length polymorphism (RFLP)-based analysis.

Results

The BAX-248GA genotype is independently associated with idiopathic RPL [adjusted OR = 0.30, 95% CI 0.13–0.70, P = 0.005] susceptibility. In the same multivariate model, the variables ethnicity, smoking, and alcohol consumption were statistically associated with RPL susceptibility (P < 0.05). No association with RPL susceptibility was reported for the remaining SNPs.

Conclusion

Our study is the first to evaluate the role of the main SNPs from both the extrinsic and intrinsic apoptosis pathways in RPL susceptibility. The association of BAX-248G/A with RPL susceptibility suggests that maternal predisposition for RPL has an essential contribution from genes involved in the delicate balance of endometrium cell turnover (cell death/proliferation). Therefore, apoptotic genes may represent promising targets for future studies on healthy pregnancies and the spectrum of pregnancy disorders.
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Literature
1.
Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98:1103–11.CrossRef
2.
3.
Christiansen OB. Research methodology in recurrent pregnancy loss. Obstet Gynecol Clin N Am. 2014;41:19–39.CrossRef
4.
Toth B, Jeschke U, Rogenhofer N, Scholz C, Würfel W, Thaler CJ, et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol. 2010;85:25–32.CrossRefPubMed
5.
Shahine L, Lathi R. Recurrent pregnancy loss. Obstet Gynecol Clin N Am. 2015;42:117–34.CrossRef
6.
Aghaeepour N, Ganio EA, Mcilwain D, Tsai AS, Tingle M, Van Gassen S, et al. An immune clock of human pregnancy. Sci Immunol. 2017;1:2.
7.
8.
Choi H-K, Choi BC, Lee S-H, Kim JW, Cha KY, Baek K-H. Expression of angiogenesis- and apoptosis-related genes in chorionic villi derived from recurrent pregnancy loss patients. Mol Reprod Dev. 2003;66:24–31.CrossRefPubMed
9.
Baek K-H. Aberrant gene expression associated with recurrent pregnancy loss. Mol Hum Reprod. 2004;10:291–7.CrossRefPubMed
10.
Sõber S, Rull K, Reiman M, Ilisson P, Mattila P, Laan M. RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery. Sci Rep. 2016;6:38439.CrossRefPubMedPubMedCentral
11.
Lee J, Oh J, Choi E, Park I, Han C, Kim DH, et al. Differentially expressed genes implicated in unexplained recurrent spontaneous abortion. Int J Biochem Cell Biol. 2007;39:2265–77.CrossRefPubMed
12.
Krieg SA, Fan X, Hong Y, Sang Q-X, Giaccia A, Westphal LM, et al. Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss. Mol Hum Reprod. 2012;18:442–50.CrossRefPubMedPubMedCentral
13.
Wei D, Wu Q, Shi H. Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion. Exp Ther Med. 2014;7:191–4.CrossRefPubMed
14.
Oreshkova T, Dimitrov R, Mourdjeva M. A cross-talk of decidual stromal cells, trophoblast, and immune cells: a prerequisite for the success of pregnancy. Am J Reprod Immunol. 2012;68:366–73.CrossRefPubMed
15.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25:486–541.CrossRefPubMedPubMedCentral
16.
Peter ME, Hadji A, Murmann AE, Brockway S, Putzbach W, Pattanayak A, et al. The role of CD95 and CD95 ligand in cancer. Cell Death Differ. 2015;22:549–59.CrossRefPubMedPubMedCentral
17.
Murakoshi H, Matsuo H, Laoag-Fernandez JB, Samoto T, Maruo T. Expression of Fas/Fas-ligand, Bcl-2 protein and apoptosis in extravillous trophoblast along invasion to the decidua in human term placenta. Endocr J. 2003;50:199–207.CrossRefPubMed
18.
Niederkorn JY. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol. 2006;7:354–9.CrossRefPubMed
19.
Robinson R, Hsu CD, Chesebro AL, Nguyen J, Ali N, Maramreddy H, et al. A single-nucleotide polymorphism (-670) of the maternal Fas gene is associated with intrauterine growth restriction. Am J Obstet Gynecol. 2009;201:620.e1–4.CrossRef
20.
Ciarmela P, Boschi S, Bloise E, Marozio L, Benedetto C, Castellucci M, et al. Polymorphisms of FAS and FAS ligand genes in preeclamptic women. Eur J Obstet Gynecol Reprod Biol. 2010;148:144–6.CrossRefPubMed
21.
Nair RR, Khanna A, Singh K. Association of FAS-1377 G>A and FAS-670 A>G functional polymorphisms of FAS gene of cell death pathway with recurrent early pregnancy loss risk. J Reprod Immunol. 2012;93:114–8.CrossRefPubMed
22.
Banzato PCA, Daher S, Traina É, Torloni MR, Gueuvoghlanian-Silva BY, Puccini RF, et al. FAS and FAS-L genotype and expression in patients with recurrent pregnancy loss. Reprod Sci. 2013;20:1111–5.CrossRefPubMedPubMedCentral
23.
Nasr AS, Abdel Aal AA, Soliman A, Setohy KAAEL, Shehata MF. FAS and FAS ligand gene polymorphisms in Egyptian females with preeclampsia. J Reprod Immunol. 2014;104–105:63–7.CrossRefPubMed
24.
Glesse N, Vianna P, Paim LMG, Matte MCC, Aguiar AKK, Palhano PL, et al. Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus. Lupus. 2017;26:746–55.CrossRefPubMed
25.
Raguema N, Zitouni H, Ben Ali Gannoun M, Benletaifa D, Almawi W, Mahjoub T, et al. FAS A-670G and Fas ligand IVS2nt A 124G polymorphisms are significantly increased in women with pre-eclampsia and may contribute to HELLP syndrome: a case-controlled study. BJOG. 2018;125:1758–64.CrossRefPubMed
26.
Masoumi E, Tavakkol-Afshari J, Nikpoor AR, Ghaffari-Nazari H, Tahaghoghi-hajghorbani S, Jalali SA. Relationship between Fas and Fas ligand gene polymorphisms and pre-eclampsia. J Obstet Gynaecol Res. 2016;42:1272–8.CrossRefPubMed
27.
Han AR, Choi YM, Hong MA, Kim JJ, Lee SK, Yang KM, et al. Fas and FasL genetic polymorphisms in women with recurrent pregnancy loss: a case-control study. Hum Fertil. 2018:1–6.
28.
Huang QR, Morris D, Manolios N. Identification and characterisation of polymorphisms in the promoter region of the human Apo-1/Fas (CD95) gene. Mol Immunol. 1997;34:577–82.CrossRefPubMed
29.
Sibley K, Rollinson S, Allan JM, Smith AG, Law GR, Roddam PL, et al. Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res. 2003;63:4327–30.PubMed
30.
Wu J, Metz C, Xu X, Abe R, Gibson AW, Edberg JC, et al. A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol. 2003;170:132–8.CrossRefPubMed
31.
Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G. Mitochondrial control of cellular life, stress, and death. Circ Res. 2012;111:1198–207.CrossRefPubMed
32.
Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, et al. Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis. Cell. 2005;121:579–91.CrossRefPubMed
33.
Marie Hardwick J, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5:a008722.PubMed
34.
Nückel H, Frey UH, Bau M, Sellmann L, Stanelle J, Dürig J, et al. Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. Blood. 2007;109:290–7.CrossRefPubMed
35.
Sahu SK, Choudhuri T. Lack of association between Bax promoter (-248G>A) single nucleotide polymorphism and susceptibility towards cancer: evidence from a meta-analysis. PLoS One. 2013;8(10):e77534.CrossRefPubMedPubMedCentral
36.
Feng Y, Chen X, Zheng Y, Liu Q, Chen H, Cai Y, et al. Prognostic value and susceptibility of BAX rs4645878 polymorphism in cancer. Medicine (Baltimore). 2018;97:e11591.CrossRef
37.
Skogsberg Å, Tobin G, Kröber A, Kienle D, Thunberg U, Åleskog A, et al. The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia. Leukemia. 2006;20:77–81.CrossRefPubMed
38.
Moshynska O, Sankaran K, Saxena A. Molecular detection of the G(-248)A BAX promoter nucleotide change in B cell chronic lymphocytic leukaemia. Mol Pathol. 2003;56:205–9.CrossRefPubMedPubMedCentral
39.
Starczynski J, Pepper C, Pratt G, Hooper L, Thomas A, Milligan D, et al. Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic leukemia once treatment is initiated. J Clin Oncol. 2005;23:1514–21.CrossRefPubMed
40.
Fegan C, Starczynski J, Pratt G, Pepper C. The role of the bax gene polymorphism G(-248)A in chronic lymphocytic leukemia. Leukemia. 2006;20:1460–1.CrossRefPubMed
41.
Shang W, Shu M-M, Liu M, Wang A-M, Lv L-B, Zhao Y, et al. Elevated expressions of p53, CDKNA1, and Bax in placental villi from patients with recurrent spontaneous abortion. Eur Rev Med Pharmacol Sci. 2013;17:3376–80.PubMed
42.
Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association Studies (STREGA)—an extension of the STROBE statement. PLoS Med. 2009;3:6:e22.
43.
44.
Sun T, Miao X, Zhang X, Tan W, Xiong P, Lin D. Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J Natl Cancer Inst. 2004;96:1030–6.CrossRefPubMed
45.
Zhang Z, Wang L-E, Sturgis EM, El-Naggar AK, Hong WK, Amos CI, et al. Polymorphisms of FAS and FAS ligand genes involved in the death pathway and risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2006;12:5596–602.CrossRefPubMed
46.
Zhang N, Li X, Tao K, Jiang L, Ma T, Yan S, et al. BCL-2 (-938C > A) polymorphism is associated with breast cancer susceptibility. BMC Med Genet. 2011;12:48.CrossRefPubMedPubMedCentral
47.
Rodriguez S, Gaunt TR, Day INM. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–14.CrossRefPubMedPubMedCentral
48.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.CrossRefPubMed
49.
Kroeff LR, Mengue SS, Schmidt MI, Duncan BB, Favaretto ALF, Nucci LB. Fatores associados ao fumo em gestantes avaliadas em cidades brasileiras. Rev Saude Publica. 2004;38:261–7.CrossRefPubMed
50.
Ruiz-Linares A, Adhikari K, Acuña-Alonzo V, Quinto-Sanchez M, Jaramillo C, Arias W, et al. Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals. PLoS Genet. 2014;10:e1004572.CrossRefPubMedPubMedCentral
51.
Gilbert-Diamond D, Moore JH. Analysis of gene-gene interactions. Curr Protoc Hum Genet. 2011;1:Unit1.14.PubMed
52.
Kalish RB, Nguyen DP, Vardhana S, Gupta M, Perni SC, Witkin SS. A single nucleotide A>G polymorphism at position -670 in the Fas gene promoter: relationship to preterm premature rupture of fetal membranes in multifetal pregnancies. Am J Obstet Gynecol. 2005;192:208–12.CrossRefPubMed
53.
Sezgin M, Barlas IÖ, Yildir S, Türköz G, Ankarali HÇ, Şahin G, et al. Apoptosis-related Fas and FasL gene polymorphisms’ associations with knee osteoarthritis. Rheumatol Int. 2013;33:2039–43.CrossRefPubMed
54.
Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril. 2010;93:1234–43.CrossRefPubMed
55.
Bhattacharya S, Townend J, Bhattacharya S. Recurrent miscarriage: are three miscarriages one too many? Analysis of a Scottish population-based database of 151,021 pregnancies. Eur J Obstet Gynecol Reprod Biol. 2010;150:24–7.CrossRefPubMed
56.
57.
Krieg SA, Shahine LK, Lathi RB. Environmental exposure to endocrine-disrupting chemicals and miscarriage. Fertil Steril. 2016;106:941–7.CrossRefPubMed
58.
Conforti A, Mascia M, Cioffi G, De Angelis C, Coppola G, De Rosa P, et al. Air pollution and female fertility: a systematic review of literature. Reprod Biol Endocrinol. 2018;16:117.CrossRefPubMedPubMedCentral
59.
Mukherjee S, Velez Edwards DR, Baird DD, Savitz DA, Hartmann KE. Risk of miscarriage among black women and white women in a U.S. Prospective Cohort Study. Am J Epidemiol. 2013;177:1271–8.CrossRefPubMedPubMedCentral
60.
Harb HM, Al-rshoud F, Dhillon R, Harb M, Coomarasamy A. Ethnicity and miscarriage: a large prospective observational study and meta-analysis. Fertil Steril. 2014;102:e81.CrossRef
61.
Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake in pregnancy and the risk of spontaneous abortion. Alcohol Alcohol. 2002;37:87–92.CrossRefPubMed
62.
Lindbohm M-L, Sallmén M, Taskinen H. Effects of exposure to environmental tobacco smoke on reproductive health. Scand J Work Environ Health. 2002;28(Suppl 2):84–96.PubMed
63.
Wikström A-K, Stephansson O, Cnattingius S. Tobacco use during pregnancy and preeclampsia risk. Hypertension. 2010;55:1254–9.CrossRefPubMed
64.
Jeyabalan A, Powers RW, Durica AR, Harger GF, Roberts JM, Ness RB. Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia. Am J Hypertens. 2008;21:943–7.CrossRefPubMedPubMedCentral
65.
66.
Kawashima A, Koide K, Ventura W, Hori K, Takenaka S, Maruyama D, et al. Effects of maternal smoking on the placental expression of genes related to angiogenesis and apoptosis during the first trimester. Zenclussen AC, editor. PLoS One. 2014;9:e106140.CrossRefPubMedPubMedCentral
67.
Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80:293–9.CrossRefPubMed
68.
Chen K, Hu Z, Wang LE, Sturgis EM, El-naggar AK, Zhang W, et al. Single-nucleotide polymorphisms at the TP53-binding or responsive promoter regions of BAX and BCL2 genes and risk of squamous cell carcinoma of the head and neck. Carcinogenesis. 2007;28:2008–12.CrossRefPubMed
69.
Fraga LR, Dutra CG, Boquett JA, Vianna FSL, Gonçalves RO, Paskulin DD, et al. p53 signaling pathway polymorphisms associated to recurrent pregnancy loss. Mol Biol Rep. 2014;41:1871–7.CrossRefPubMed
70.
Vaskivuo TE, Stenbäck F, Karhumaa P, Risteli J, Dunkel L, Tapanainen JS. Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol. 2000;165:75–83.CrossRefPubMed
71.
De Falco M, De Luca L, Acanfora F, Cavallotti I, Cottone G, Laforgia V, et al. Alteration of the Bcl-2:Bax ratio in the placenta as pregnancy proceeds. Histochem J. 2001;33:421–5.CrossRefPubMed
Metadata
Title
The role of FAS, FAS-L, BAX, and BCL-2 gene polymorphisms in determining susceptibility to unexplained recurrent pregnancy loss
Authors
Rafael Tomoya Michita
Francis Maria Báo Zambra
Lucas Rosa Fraga
Maria Teresa Sanseverino
Lavínia Schuler-Faccini
José Artur Bogo Chies
Priscila Vianna
Publication date
01-05-2019
Publisher
Springer US
Keyword
Miscarriage
Published in
Journal of Assisted Reproduction and Genetics / Issue 5/2019
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-019-01441-w

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