Genetic variants of progesterone receptor in etiology of preterm delivery
, 12, 1, 1, 1, 3, 4, 5, 12
Abstract
Objectives: Preterm delivery (PTD) accounts for around 11% of pregnancies worldwide. Unfortunately, no diagnostic
indicator, specific mechanism or genetic predisposition has yet been identified. One of the hypotheses suggest local or
functional progesterone decrease as a potential reason for preterm uterine contractions leading to preterm delivery. It is
believed that any change in progesterone receptor DNA may be crucial for higher risk of preterm delivery due to abnormal response to prostaglandins, normally inhibited by properly built progesterone. The aim of this study was to determine whether there is an association between progesterone gene polymorphisms (PROGINS and +331G/A) and preterm birth.
Material and methods: A total of 230 women were enrolled, including 115 cases of preterm deliveries (between 22
and 36 weeks of gestation) and 115 healthy mothers of full-term infants. Genomic DNA was isolated from the blood
sample. Polymerase chain reaction (PCR) amplification was carried out in a final volume of 25 μL. Genotyping was assayed by PCR. Statistical analysis of the results was conducted with p < 0.05 accepted as statistically significant.
Results: For both PROGINS (Alu ins/del) and +331G/A (rs10895068) polymorphisms were equally frequent in case
and control group. The prevalence of PGR alleles in both groups was also comparable.
Conclusions: The results of our study showed no association between progesterone gene polymorphisms (PROGINS
and +331G/A) and risk of preterm delivery. Identifying mechanisms to prolong the length of gestation, particularly in
women at risk for preterm delivery, will improve both maternal and fetal outcomes.
Keywords: genetic polymorphismpreterm deliveryprogesterone receptor gene
References
- Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012; 379(9832): 2162–2172.
- McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med. 1985; 312(2): 82–90.
- Fitzmaurice C, Allen C, Barber RM, et al. Global Burden of Disease Cancer Collaboration. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3(4): 524–548.
- Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG. 2006; 113 Suppl 3: 17–42.
- Meis PJ, Klebanoff M, Thom E, et al. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003; 348(24): 2379–2385.
- Gibb W, Challis J. Mechanisms of Term and Preterm Birth. Journal of Obstetrics and Gynaecology Canada. 2002; 24(11): 874–883.
- Jacobsen BM, Schittone SA, Richer JK, et al. Progesterone-independent effects of human progesterone receptors (PRs) in estrogen receptor-positive breast cancer: PR isoform-specific gene regulation and tumor biology. Mol Endocrinol. 2005; 19(3): 574–587.
- Kotsopoulos J, Tworoger SS, De Vivo I, et al. +331G/A variant in the progesterone receptor gene, postmenopausal hormone use and risk of breast cancer. Int J Cancer. 2009; 125(7): 1685–1691.
- Yang DS, Sung HJ, Woo OkH, et al. Association of a progesterone receptor gene +331 G/A polymorphism with breast cancer risk: a meta-analysis. Cancer Genet Cytogenet. 2010; 196(2): 194–197.
- Pabalan N, Salvador A, Jarjanazi H, et al. Association of the progesterone receptor gene polymorphism (PROGINS) with endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014; 290(5): 1015–1022.
- Romano A, Lindsey PJ, Fischer DC, et al. Two functionally relevant polymorphisms in the human progesterone receptor gene (+331 G/A and progins) and the predisposition for breast and/or ovarian cancer. Gynecol Oncol. 2006; 101(2): 287–295.
- Rowe SM, Coughlan SJ, McKenna NJ, et al. Ovarian carcinoma-associated TaqI restriction fragment length polymorphism in intron G of the progesterone receptor gene is due to an Alu sequence insertion. Cancer Res. 1995; 55(13): 2743–2745.
- Kieback D, Tong X, Weigel N, et al. A Genetic Mutation in the Progesterone Receptor (PROGINS) leads to an increased risk of non-familial breast and ovarian cancer causing inadequate control of estrogen receptor driven proliferation. J Soc Gynecol Investig. 1998; 5(1): 40A.
- Rowe SM, Coughlan SJ, McKenna NJ, et al. A germline TaqI restriction fragment length polymorphism in the progesterone receptor gene in ovarian carcinoma. Br J Cancer. 1995; 71(3): 451–455.
- De Vivo I, Huggins GS, Hankinson SE, et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A. 2002; 99(19): 12263–12268.
- Sfakianaki AK, Norwitz ER. Mechanisms of progesterone action in inhibiting prematurity. J Matern Fetal Neonatal Med. 2006; 19(12): 763–772.
- Challis JRG, Matthews SG, Gibb W, et al. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev. 2000; 21(5): 514–550.
- Lancaster JM, Berchuck A, Carney ME, et al. Progesterone receptor gene polymorphism and risk for breast and ovarian cancer. Br J Cancer. 1998; 78(2): 277.
- Li D, Cheng J, Li W, et al. Association between male infertility and either the +331G/A or the progins polymorphism of the progesterone receptor gene in a Chinese population. Iran J Reprod Med. 2015; 13(1): 35–40.
- Team RA. language and environment for statistical computing. Computing. 2002; 2006: 1.
- González JR, Armengol L, Solé X, et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007; 23(5): 644–645.
- Su MT, Lin SH, Chen YC. Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2011; 96(6): 1435–1444.e1.
- Schweikert A, Rau T, Berkholz A, et al. Association of progesterone receptor polymorphism with recurrent abortions. Eur J Obstet Gynecol Reprod Biol. 2004; 113(1): 67–72.
- Su MT, Lee IW, Chen YC, et al. Association of progesterone receptor polymorphism with idiopathic recurrent pregnancy loss in Taiwanese Han population. J Assist Reprod Genet. 2011; 28(3): 239–243.
- Leite DB, Junqueira MG, de Carvalho CV, et al. Progesterone receptor (PROGINS) polymorphism and the risk of ovarian cancer. Steroids. 2008; 73(6): 676–680.
- Liu T, Chen L, Sun X, et al. Progesterone receptor PROGINS and +331G/A polymorphisms confer susceptibility to ovarian cancer: a meta-analysis based on 17 studies. Tumour Biol. 2014; 35(3): 2427–2436.
- Yuan C, Wang C, Liu X, et al. Analyze association of the progesterone receptor gene polymorphism PROGINS with ovarian cancer risk. Mol Biol Rep. 2013; 40(10): 6001–6010.
- Pijnenborg JMA, Romano A, Dam-de Veen GC, et al. Aberrations in the progesterone receptor gene and the risk of recurrent endometrial carcinoma. J Pathol. 2005; 205(5): 597–605.
- Oliveira TA, da Cunha DR, Policastro A, et al. [The progesterone receptor gene polymorphism as factor of risk for the preterm delivery]. Rev Bras Ginecol Obstet. 2011; 33(6): 271–275.
- Luo G, Morgan T, Bahtiyar MO, et al. Single nucleotide polymorphisms in the human progesterone receptor gene and spontaneous preterm birth. Reprod Sci. 2008; 15(2): 147–155.
- Tiwari D, Bose PD, Das S, et al. MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study. Meta Gene. 2015; 3: 31–42.
- Ehn NL, Cooper ME, Orr K, et al. Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth. Pediatr Res. 2007; 62(5): 630–635.
- Diaz-Cueto L, Dominguez-Lopez P, Cantillo-Cabarcas J, et al. Progesterone receptor gene polymorphisms are not associated with preterm birth in a Hispanic population. Int J Gynaecol Obstet. 2008; 103(2): 153–157.
