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Genetic Variation Within the Hypothalamus-Pituitary-Ovarian Axis in Women with Recurrent Miscarriage

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Genetic Variation Within the Hypothalamus-Pituitary-Ovarian Axis in Women with Recurrent Miscarriage Hum. Reprod. Advance Access published August 17, 2010 Human Reproduction, Vol.00, No.0 pp. 1–8, 2010 doi:10.1093/humrep/deq211 ORIGINAL ARTICLE Reproductive Genetics Genetic variation within the hypothalamus-pituitary-ovarian axis in women with recurrent miscarriage Courtney W. Hanna1,2, Karla L. Bretherick3, Chi-Chao Liu2, Mary D. Stephenson4,5, and Wendy P. Robinson1,2,* 1Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada 2Child and Family Research Institute, 950 W. 28th Ave, Room 3086, Vancouver, British Columbia V5Z 4H4, Canada 3Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada 4Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA 5Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Downloaded from Canada *Correspondence address. E-mail: [email protected] Submitted on March 15, 2010; resubmitted on July 16, 2010; accepted on July 21, 2010 http://humrep.oxfordjournals.org/ background: Recurrent miscarriage affects 1–2% of couples trying to conceive, and is idiopathic in nearly half. Female fertility is con- trolled by the hypothalamus-pituitary-ovarian (HPO) axis and we hypothesize that genetic polymorphisms affecting the function of genes involved in regulating the HPO axis will be associated with recurrent miscarriage. methods: Whole peripheral blood DNA from 227 women with recurrent miscarriage and 130 control women was obtained for this study. Using the Sequenom iPlex assay for fragment analysis, 31 single-nucleotide polymorphisms (SNPs) and 4 short tandem repeat (STR) polymorphisms in 20 candidate genes were evaluated for genetic association with recurrent miscarriage. results: Several candidate associations were identified with an uncorrected P-value of 0.05. Genotype distribution at an SNP (rs37389) in the prolactin receptor gene (P ¼ 0.03), and allele distributions at an SNP (rs41423247) in the glucocorticoid receptor gene (P ¼ 0.04) and by guest on February 20, 2014 an STR polymorphism in the estrogen receptor b gene (P ¼ 0.03) were associated with recurrent miscarriage. The T allele of an SNP (rs2033962) within the activin receptor type 1 gene (ACVR1) was associated with increased number of miscarriages in an additive manner (P ¼ 0.02). These candidate associations were not statistically significant after correcting for multiple analyses. conclusions: Candidate associations were identified between recurrent miscarriage and genetic variation within ESR2, PRLR, GCCR and ACVR1 genes. Independent confirmation of these results is needed, as limitations of this study include the heterogeneous etiology of recurrent miscarriage, limited sample size, partial availability of reproductive history of the control group and investigation of only a subset of the genetic variation within each gene. Key words: hypothalamus-pituitary-ovarian axis / hormone receptors / recurrent miscarriage / infertility / SNP analysis Introduction the hypothalamus-pituitary-ovarian (HPO) axis. This feedback loop begins with gonadotrophin-releasing hormone being released from Recurrent miscarriage, three or more consecutive miscarriages, occurs the hypothalamus, resulting in the secretion of the gonadotrophins at a rate of 1–2% of couples trying to conceive (Stirrat, 1990). There (LH and FSH) from the anterior pituitary, which in turn controls estro- are several known factors associated with risk for recurrent miscar- gen and progesterone production in the ovaries (Djahanbakhch et al., riage, including genetic, endocrine, autoimmune, anatomical, thrombo- 2007). Estrogen and progesterone play a central role in female fertility philic and infectious (Li et al., 2002; Rai and Regan, 2006). These by stimulating growth, differentiation and maturation of follicles, pre- factors vary in frequency, depending on maternal age and population paring the endometrium for implantation (Drummond and Findlay, studied, however, these can only be identified in 50–60% of cases 1999) and maintaining embryonic development (Schindler, 2005). (Stephenson, 1996; Li et al., 2002), leaving almost half of women Altered levels of hormones and other factors that are involved in with idiopathic recurrent miscarriage. maintaining control of the HPO axis can have negative effects on fer- The female reproductive system, including sexual differentiation, tility and pregnancy. Elevated levels of gonadotrophins and estradiol menstrual cycling and the early stages of pregnancy, is controlled by have been previously associated with recurrent miscarriage (Li et al., & The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected] 2 Hanna et al. 2000; Gu¨rbu¨z et al., 2003,2004). Elevated FSH is seen with advancing maternal age and is indicative of reduced ovarian responsiveness (Fitz- Table I Comparison of allele distributions between womenwithrecurrentmiscarriage(n 5 227) and gerald et al., 1998). Endocrine disorders such as polycystic ovarian syn- controls (n 5 130) for microsatellite polymorphisms drome and luteal phase deficiency are associated with increased rates within hormone receptors. of miscarriage due to altered progesterone and estrogen production in the ovary (Li, 1998). During the first 2 months of pregnancy, the Allele Recurrent miscarriage Controls Obs. P-valuea primary source of progesterone and estrogen is the corpus luteum Obs. (freq.) (freq.) (Schindler, 2005), and if removed, the pregnancy will end in miscar- ........................................................................................ riage (Csapo et al., 1972). AR (androgen receptor) CAG repeat 0.631 ≤ We therefore hypothesized that genetic polymorphisms in genes 20 124 (0.27) 85 (0.33) involved in regulating the HPO axis would be associated with recurrent 21 81 (0.18) 44 (0.17) miscarriage. To investigate this, we compared genotype frequencies of 22 53 (0.12) 26 (0.10) short tandem repeats (STRs) and single-nucleotide polymorphisms 23 62 (0.14) 31 (0.12) (SNPs) in 20 genes involved in the HPO axis (Tables I and II)among ≥24 134 (0.30) 74 (0.28) women with recurrent miscarriage and controls. Polymorphisms ESR1 (Estrogen receptor a) TA repeat 0.250 assayed include those that have been previously reported to affect tran- ≤13 47 (0.10) 24 (0.10) scription, hormone levels or reproductive outcome. 14 135 (0.30) 87 (0.34) Downloaded from 15 54 (0.12) 19 (0.07) Materials and Methods 16 13 (0.03) 11 (0.04) 17–20 46 (0.10) 21 (0.08) Samples 21 45 (0.10) 23 (0.09) A total of 357 women were recruited from a Western Canadian popu- 22 28 (0.06) 26 (0.10) http://humrep.oxfordjournals.org/ lation at the BC Women’s Hospital & Health Centre in Vancouver, 23 37 (0.08) 25 (0.10) British Columbia. The case group consisted of 227 women with recurrent ≥24 49 (0.11) 24 (0.09) miscarriage (all evaluated by a single physician, M.D.S.), defined as three or ESR2 (Estrogen receptor b) CA repeat 0.026 more consecutive miscarriages before 20 weeks of gestation. This recur- rent miscarriage group had a mean age at time of pregnancy (standard ≤18 74 (0.16) 33 (0.13) deviation; range) of 31.4 (6.1; 15–40) years with a total of 1379 pregnan- 19 25 (0.06) 20 (0.08) cies, of which 1027 (75%) ended in miscarriage. The mean number of mis- 20 11 (0.02) 15 (0.06) carriages (standard deviation; range) was 4.5 (1.9; 3–13). Chromosome 21 32 (0.07) 17 (0.07) results were obtained in 208 of these miscarriages, of which 110 (53%) 22 52 (0.12) 45 (0.17) by guest on February 20, 2014 were euploid, with a 46,XX/46,XY ratio of 0.80 (49/61). Ninety eight (47%) of the miscarriages were karyotypically abnormal, including 70 auto- 23 164 (0.36) 76 (0.29) somal trisomies, 16 polyploidies, 3 polyploidies with trisomies, 4 unba- ≥24 96 (0.21) 54 (0.21) lanced translocations, 3 monosomy X (45,X), 1 monosomy X and SHBG (Sex hormone-binding globulin) TAAAA repeat 0.511 trisomy 21 and 1 sex chromosome trisomy (47,XXY). Carriers of a struc- ≤6 121 (0.27) 61 (0.23) tural chromosome rearrangement were excluded from this study. Forty 7 31 (0.07) 23 (0.09) (18%) of the 227 women with recurrent miscarriage had concomitant 8 149 (0.33) 95 (0.38) infertility. The control group used in this study consisted of 130 women of repro- 9 111 (0.24) 63 (0.24) ductive age. Proven fertility and/or regular menstrual cycles were known ≥10 42 (0.10) 18 (0.07) in 67 of these women with a mean (standard deviation, range) menstrual a cycle length of 28.4 (2.1; 23–35) days. Women with a known history of Chi-square analysis. miscarriage, infertility or abnormal cycles were excluded from this study group. Reproductive history was unknown in the remaining 63 women; however, inclusion of these controls will only marginally reduce the be associated with reduced fertility in women and/or altered HPO power, as few will have irregular cycles and/or recurrent miscarriage. axis hormone levels. In some cases, published polymorphisms could On the basis of the 357 subjects, with a power of 0.80 and an a of not be utilized due to technical constraints on the applied assay design 0.05, an effect size of 0.16 can be observed in this study (Faul et al., 2007). in the current study (Sequenom iPlex) or due to limited available The collection of the samples for this study was approved by the Uni- information. versity of British Columbia Clinical Ethics Review Board. To assess the possibility of population stratification, a difference in ethnic distribution between cases and controls, as a confounding factor Variant selection in this study, 23 ancestral informative SNPs were chosen to assay in Candidate genes in this study were identified through a literature search, cases and controls, as described by Kosoy et al. (2009). using the search words ‘recurrent miscarriage’, ‘fertility’ and ‘female reproduction’.
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