Journal of Obstetrics and Gynaecology
ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20
Prolactin receptor gene polymorphism and the risk of recurrent pregnancy loss: a case-control study Jin Ju Kim, Young Min Choi, Sung Ki Lee, Kwang Moon Yang, Eun Chan Paik, Hyeon Jeong Jeong, Jong Kwan Jun, Ae Ra Han, Kyu Ri Hwang & Min A Hong To cite this article: Jin Ju Kim, Young Min Choi, Sung Ki Lee, Kwang Moon Yang, Eun Chan Paik, Hyeon Jeong Jeong, Jong Kwan Jun, Ae Ra Han, Kyu Ri Hwang & Min A Hong (2017): Prolactin receptor gene polymorphism and the risk of recurrent pregnancy loss: a case-control study, Journal of Obstetrics and Gynaecology, DOI: 10.1080/01443615.2017.1351932 To link to this article: http://dx.doi.org/10.1080/01443615.2017.1351932
Published online: 05 Oct 2017.
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Date: 13 October 2017, At: 20:24
JOURNAL OF OBSTETRICS AND GYNAECOLOGY, 2017 https://doi.org/10.1080/01443615.2017.1351932
ORIGINAL ARTICLE
Prolactin receptor gene polymorphism and the risk of recurrent pregnancy loss: a case-control study Jin Ju Kima,b, Young Min Choib,c , Sung Ki Leed, Kwang Moon Yange, Eun Chan Paikf, Hyeon Jeong Jeongg, Jong Kwan Junb, Ae Ra Hand, Kyu Ri Hwangh and Min A Hongb
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a Department of Obstetrics and Gynecology, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea; bThe Institute of Reproductive Medicine and Population, Medical Research Centre, Seoul National University College of Medicine, Seoul, Korea; c Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea; dDepartment of Obstetrics and Gynecology, Konyang University College of Medicine, Daejeon, Korea; eDepartment of Obstetrics and Gynecology, Cheil General Hospital & Women’s Healthcare Center, Dankook University College of Medicine, Seoul, Korea; fDepartment of Obstetrics and Gynecology, Bundangcheil Women’s Hospital, Bundang, Korea; gDepartment of Obstetrics and Gynecology, Seoul Rachel Fertility Center, Seoul, Korea; hDepartment of Obstetrics and Gynecology, Seoul Municipal Boramae Hospital, Seoul, Korea
KEYWORDS
ABSTRACT
Since the first study was published reporting the candidate association between the prolactin receptor gene intron C/T polymorphism (rs37389) and recurrent miscarriage, no replication study has been performed. In this study, we investigated the role of the prolactin receptor gene C/T polymorphism in 311 Korean women with recurrent pregnancy loss and 314 controls. Genotyping for prolactin receptor gene intron C/T polymorphism was performed using a TaqMan assay. The significance of difference in the genotype distribution was assessed using a chi-square test, and continuous variables were compared using a Student’s t-test. The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent pregnancy loss group did not differ from that in the control group (CC/CT/TT rates were 49.8%/41.5%/8.7% and 52.5%/37.6%/9.9% for the recurrent pregnancy loss patient and control groups, respectively, p ¼ .587). When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages or patients without prior live birth, there were also no differences in the genotype distribution between these subgroups and controls. In conclusion, the findings of the current study suggest that the prolactin receptor gene intron C/T polymorphism is not a major determinant of the development of recurrent pregnancy loss.
Miscarriage; prolactin receptor gene; recurrent pregnancy loss; singlenucleotide polymorphism
IMPACT STATEMENT
What is already known: Many studies have investigated whether there is a genetic component for the risk of recurrent pregnancy loss. Recently, one study investigated whether genetic polymorphisms involved in the regulation of the hypothalamic-pituitary-ovarian axis would be associated with recurrent miscarriage. Among 35 polymorphisms in 20 candidate genes, genotype distribution with regard to the prolactin receptor gene intron C/T polymorphism (rs37389) differed between the recurrent miscarriage and the control groups. Since this study reporting the candidate association between the prolactin receptor gene and recurrent miscarriage, no replication study has been performed. What the results of this study add: The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent miscarriage group did not differ from that in the control group. What the implications are of these findings: Our study may be useful in that it is the first replication study since the initial report of the association of prolactin receptor gene polymorphism with recurrent miscarriage. Although no association was found, the potential role of prolactin in pregnancy loss needs to be further investigated because prolactin and its receptor have been postulated to play an important role in the maintenance of normal pregnancy.
Introduction Recurrent pregnancy loss (RPL) is defined as two or more consecutive spontaneous miscarriages, usually before 20 weeks of gestation (Practice Committee of the American Society for Reproductive Medicine 2013). Various factors, including genetic, anatomical and endocrine defects, have been postulated as being causes of RPL, but in most cases,
the causes remain unexplained (Coulam et al. 1997; Park et al. 2011; Kim et al. 2014). Prolactin is known for its role in the process of breast development and lactation, and prolactin exerts its effects by binding the prolactin receptor (PRL-R). Prolactin is primarily secreted by the anterior pituitary, but extra pituitary expression is known. During pregnancy, the decidualised
CONTACT Young Min Choi
[email protected] Department of Obstetrics and Gynecology, The Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University College of Medicine 28 Yungun-dong, Chongno-ku, Seoul 110-744, Korea ß 2017 Informa UK Limited, trading as Taylor & Francis Group
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endometrial stroma is the site of prolactin synthesis (Wu et al. 1995). In a non-pregnant state, expression of prolactin and PRL-R during the mid-to-late secretory phase in the endometrium was reported (Jabbour et al. 1998; Jones et al. 1998). A potential association between recurrent miscarriage and prolactin or PRL-R has been reported. Garzia et al. (2004) found a lack of expression of endometrial prolactin during the ‘implantation window’ in women with repeated miscarriages. Bersinger et al. (2008) also reported the down-regulation of the PRL-R in the endometrium of women with miscarriage. An animal study found that a lack of PRL-R was associated with the failure of embryonic implantation or defective preimplantation embryonic development, and PRL-R is an essential component for endometrial receptivity (Ormandy et al. 1997). These findings may indicate that prolactin and PRL-R not only have a classic role in lactation but also have a role in the implantation process and in pregnancy maintenance. Many studies have investigated whether there is a genetic component for risk of recurrent abortion. A single gene located in chromosome 5 encodes the human PRL-R, and the PRL-R gene has been found to be expressed in the human ovary, liver and breast tissue (Hu et al. 1999; Vlahos et al. 2001; Hu et al. 2002). In 2010, Hanna et al. investigated whether genetic polymorphisms involved in the regulation of the hypothalamic-pituitary-ovarian (HPO) axis would be associated with RPL. Among the 31 single-nucleotide polymorphisms (SNPs) and the 4 short tandem repeat (STR) polymorphisms in 20 candidate genes, genotype distribution with regard to the PRL-R gene differed between the RPL group and the control group. A C/T polymorphism (rs37389) exists in the intron region, and in Hanna et al.’s study, women with recurrent miscarriage had an excess of heterozygotes (20% versus 12%) and a low frequency of homozygotes (frequencies of the CC genotype were 78% versus 83% and those of the TT genotype were 2% versus 5% in RPL patients and controls, respectively, p ¼ .028). However, no other study has been performed to examine whether this candidate gene is associated with recurrent miscarriage. Thus, we performed a replication study in an independent population to investigate the role of the PRL-R gene C/T polymorphism in 311 patients with RPL and 314 controls.
Materials and methods Subjects From March 2012 to October 2014, Korean women with or without RPL were recruited from six reproductive clinics. We recruited a total of 311 patients with RPL who had experienced at least two unexplained consecutive spontaneous miscarriages before 20 weeks of gestation according to the definition set by the American Society for Reproductive Medicine (Practice Committee of the American Society for Reproductive Medicine 2013). Women with an established cause of miscarriage, such as an anatomic cause, a parental chromosome abnormality, an autoimmune cause (antiphospholipid antibody syndrome, systemic lupus erythematosus,
etc.), an alloimmune cause (elevated natural killer cells), or endocrine abnormalities (hypothyroidism, hyperprolactinaemia, diabetes) were excluded. A total of 314 women served as controls. Controls had two or more normal term deliveries and no history of spontaneous miscarriage. The institutional review board (IRB) for human research at each centre approved this project, and written informed consent was obtained from each participant.
Genotyping of the PRL-R gene polymorphism Genomic DNA was extracted from the peripheral blood with the Wizard DNA purification kit (Promega, Madison, WI). Genotyping of the PRL-R gene C/T polymorphisms was done, and an allelic discrimination was performed using the MGBNFQ primer/probe TaqMan assay on the ABI Prism 7500 Real Time PCR System (Applied Biosystems, Foster City, CA). Distilled water was used as a negative PCR control in each amplification, and three cases with different known PCR product lengths for each of the three genes were directly sequenced for confirmation.
Statistical analysis Power calculations were performed using Quanto v.1.2.4 software (http://biostats.usc.edu/cgi-bin/DownloadQuanto.pl). A 5% population prevalence of RPL was assumed, and minor allele frequencies were obtained from the previous study (Coulam et al. 1997; Hanna et al. 2010). Given the number of enrolled subjects (311 RPL patients and 314 controls), the power for the C/T polymorphism was 0.80 to detect an allelic odds ratio of 1.6 at an a value of 0.05. Among the controls, the genotype distribution was examined for significant departures from Hardy–Weinberg equilibrium using a chi-square goodness-of-fit test, and fulfilled the Hardy–Weinberg equilibrium. The significance of difference in the genotype distribution was assessed using a chi-square test, and continuous variables were compared using a Student’s t-test. All data analyses were performed using SPSS software (version 22.0, IBM SPSS, Armonk, NY), and two-sided p values
