Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage

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1 FERTILITY AND STERILITY VOL. 75, NO. 4, APRIL 2001 Copyright 2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage Gertrud Unfried, M.D., a Clemens Tempfer, M.D., b Christian Schneeberger, Ph.D., a Barbara Widmar, B.Sc., a Fritz Nagele, M.D., a and Johannes C. Huber, M.D. a University Hospital of Vienna, Vienna, Austria Received June 30, 2000; revised and accepted October 27, Reprint requests: Fritz Nagele, M.D., Department of Gynecologic Endocrinology and Reproductive Medicine, University of Vienna School of Medicine, Waehringer, Guertel 18-20, A-1090 Vienna, Austria (FAX: ; a Department of Gynecologic Endocrinology and Reproductive Medicine. b Department of Gynecology and Obstetrics /01/$20.00 PII S (00) Objective: Proinflammatory cytokines have been described as etiologic factors in idiopathic recurrent miscarriage. We investigated the relation between idiopathic recurrent miscarriage and polymorphisms in the gene encoding for the interleukin 1 receptor antagonist, an indigenous modulator of proinflammatory immune response. Design: Prospective case control study. Setting: Academic research institution. Patient(s): One hundred five women with a history of three or more consecutive pregnancy losses before 20 weeks of gestation and 91 healthy, postmenopausal controls with at least two live births and no history of pregnancy loss. Intervention(s): Peripheral venous puncture. Main Outcome Measure(s): Polymerase chain reaction was performed to identify the different alleles of the gene encoding for interleukin 1 receptor antagonist. Result(s): Allele frequencies among women with idiopathic recurrent miscarriage and controls were 0.34 and 0.11, respectively, for the polymorphic allele 2 (P.002; odds ratio: 7.4, confidence interval: ) and.05 and.05, respectively, for the polymorphic allele 3 (P.6; odds ratio: 1.3, confidence interval: ). Allele 2 was present in homozygous form in 9% of women with idiopathic recurrent miscarriage. In contrast, 1% of the control women were homozygous for this allele (P.001; odds ratio: 13.5, confidence interval: ). Conclusion(s): These data support a role for allele 2 of the gene encoding for interleukin 1 receptor antagonist as genetic determinant of idiopathic recurrent miscarriage. (Fertil Steril 2001;75: by American Society for Reproductive Medicine.) Key Words: Idiopathic recurrent miscarriage, risk factor, interleukin 1 receptor antagonist, polymorphism Recurrent miscarriage, defined as three or more consecutive pregnancy losses before 20 weeks of gestation, affects 0.5% to 2% of pregnant women (1, 2). A great variety of etiologic factors has been identified, among them uterine abnormalities (3), luteal-phase defect (4), hyperprolactinemia (5), hyperandrogenemia (6), hyperhomocysteinuria (7), genital infections (8), and maternal/paternal balanced translocations (9). Despite a comprehensive diagnostic workup, however, a specific cause will not be identified in 50% of cases (1). Immunologic factors are believed to be at the basis of these idiopathic recurrent miscarriages (10). Autoimmune dysfunctions, such as antiphospholipid syndrome, thyroid autoantibodies, and anti single-strand DNA autoantibodies, are found in 5% to 10% of affected women (11, 12). In addition, a growing body of evidence points to a central etiologic role of alloimmune dysfunctions in women with idiopathic recurrent miscarriage. Physiologically, the maternal immune system confronts the embryo/fetus with a hostdefense reaction, based on the recognition of paternally derived fetal and placental antigens (13). To avoid rejection of the semiallogenic embryo/fetus, the maternal immune response is thoroughly suppressed in physiologic pregnancies. A reduction of proinflammatory cytokines by T-helper cell (TH)-1/TH-2 balance shift (14), lymphatic production of progesterone-in- 683

2 duced blocking factor (15), increased production of asymmetrically glycosylated blocking antibodies (16), and fetal shutdown of maternal T-cell proliferation by supporting local catabolism of tryptophan (17) are the most prominent mechanisms to guarantee embryonic/fetal evasion of the maternal immune attack. This defense system seems to be impaired in women with recurrent miscarriage. Lower serum levels of asymmetrically glycosylated antibodies have been described among affected women (16). Moreover, a lack of the physiologic TH-1/TH-2 balance shift and elevated serum levels of proinflammatory cytokines have been found among women with recurrent miscarriage (18). Interleukin 1 (IL-1) is a central proinflammatory cytokine, produced by monocytes, macrophages, and epithelial cells (19). Secretion of IL-1 leads to a proinflammatory cascade, including TH-1 proliferation, production of tumor necrosis factor (TNF)-, interferon (IFN)-, IL-2, and IL-12. Increased production of IL-1 is a characteristic feature of autoimmune disorders, such as rheumatoid arthritis (20). IL-1- activity directly influences the severity of chronic autoimmune inflammatory diseases, such as multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis (20 22). IL-1 activity is modulated by an endogenous factor, IL-1 receptor antagonist (RA). By binding to IL-1 receptors without exerting an effector function, IL-1 RA effectively acts as a competitive antagonist for IL-1, preferably IL-1- (23). The genes encoding for both IL-1- and IL-1 RA are located on the long arm of chromosome 2 in humans (24). A polymorphism of the IL-1 RA gene (IL-1 RA), displaying different copies of an 86 base pair (bp) tandem repeat in intron 2, has been identified in 21% of a Caucasian population (25). The frequency of IL-1RA allele 2 is increased in several autoimmune or inflammatory diseases, such as vulvar vestibulitis, ulcerative colitis, alopecia areata, and psoriasis (19, 26 28). The pathophysical background of this association is unclear. Santtila et al., however, were able to demonstrate both increased IL-1 RA and IL-1- production in mononuclear cells of IL-1 RA allele 2 (IL-1 RA 2/2 ) carriers (23). In view of these data and the prominent role of proinflammatory cytokines in miscarrying women, we examined polymorphisms of the IL-1 RA gene in women with idiopathic recurrent miscarriage. MATERIALS AND METHODS Patients This study was approved by the institutional review board at the University of Vienna School of Medicine. From October 1999 to June 2000, two hundred fifty women, identified by department records as having been treated for recurrent miscarriage within the period of January 1996 and September 1999, were contacted by mail and asked to participate. One hundred six women agreed to participate. One woman had a blood sample taken, but no DNA was extracted for technical reasons. The diagnosis of idiopathic recurrent miscarriage was based on a documented history of at least three spontaneous, consecutive miscarriages with the same partner before 20 weeks of gestation. To avoid confounding by ethnicity, only white Caucasian women were included in the study and control groups. To avoid confounding by genetic admixture, only women whose parents were of the same ethnicity were included in the study and control groups. These women underwent a standard diagnostic workup to rule out a verifiable cause of the recurrent miscarriages. Diagnostic procedures included hysteroscopy, paternal and maternal karyotype, cervical cultures for chlamydia, ureaplasma, and mycoplasma, a comprehensive hormonal status, and evaluation of antiphospholipid syndrome with IgM and IgG anticardiolipin antibody assessment and lupus anticoagulant testing. Among these women, primary recurrent miscarriage was defined as no history of a pregnancy carried beyond 20 weeks of gestation. Secondary recurrent miscarriage was defined as a history of at least one pregnancy carried beyond 20 weeks of gestation. The control group consisted of 91 women with at least two live births and no history of miscarriage. Because germ line mutations do not fluctuate with age, we included only postmenopausal women in the control group. This strategy was chosen to rule out possible future miscarriages of controls after inclusion in the study. Written informed consent was obtained from participating women. Genetic Studies Blood was drawn from the antecubital vein, and DNA was extracted using the QIAGEN System (QIAamp DNA Blood Midi Kit, Hilden, Germany). DNA was stored at 4 C until analyzed. A genomic DNA fragment was amplified by the polymerase chain reaction to determine IL-1 RA genotypes. Oligonucleotide primers flanking the 86-bp repeat region in intron 2 of IL-1 RA were used. The sequence of the forward primer was 5 -CTCAGCAACACTCCTAT-3. The reverse primer sequence was 5 -TCCTGGTCTGCAGG- TAA-3 (25). Polymerase chain reaction (PCR) conditions included an initial denaturing step at 94 C for 5 minutes, followed by 30 cycles of 94 C for 1 minutes, 60 C for 1 minutes, and 70 C for 2 minutes, and a final extension at 70 C for 4 minutes. Using this PCR strategy, the common allele (allele 1) generated a 410-bp band (including four copies of an 86-bp repeat). The uncommon alleles generated a 240-bp band (two copies of the same repeat; allele 2) and a 500-bp band (five copies of the same repeat; allele 3). PCR products were resolved on a 3% agarose gel and stained with SYBR Green I (FMC Bio Products Europe, Vallensbaek Strand, Denmark; Figure 1). 684 Unfried et al. An IL1-RA polymorphism and recurrent miscarriage Vol. 75, No. 4, April 2001

3 FIGURE 1 Photograph of a 3% agarose gel used to resolve the alleles 1, 2, and 3 of IL-1 RA. Lane 1: the homozygous allele 2 pattern (IL-1 RA 2/2 ). Lane 2: the heterozygous pattern for allele 1/allele 3 (IL-1 RA 1/3 ). Lane 3: the homozygous allele 1 pattern (IL-1RA 1/1 ). Statistical Analysis Differences in the frequencies of the IL-1 RA alleles in the study and control groups were analyzed by use of Fisher s exact test. The odds ratio (OR) was used as a measure of the strength of the association between allele frequencies and recurrent idiopathic miscarriage. All P values were twotailed, and 95% confidence intervals (CI) were calculated. A P value of.05 was considered statistically significant. RESULTS One hundred five women with idiopathic recurrent miscarriage and 91 control women have been examined. Characteristics of women with idiopathic recurrent miscarriage are shown in Table 1. The distribution of genotype frequencies was significantly different between the study and control groups with respect to allele 2 heterozygotes (IL-1 RA 1/2 ; 25% vs. 11%; P.01; OR, 4.2; 95% CI, ) and allele 2 homozygotes (IL-1 RA 2/2 ; 9% vs. 1%; P.001; OR, 13.5; 95% CI, ). No statistically significant difference was observed between the study and control groups with respect to allele 3 heterozygotes (IL-1 RA 1/3 ; 4% vs. 3%; P.1; OR, 1.1; 95% CI, ). Two women in the control group were found to be homozygous for allele 3 (IL-1 RA 3/3 ), and one woman in the study group was found to be heterozygous for allele 2 and allele 3 (IL-1 RA 2/3 ). The allele frequencies of IL-1 RA wild-type and polymorphic alleles in the study and control groups and the associated ORs are shown in Table 2. Between women with primary and secondary recurrent miscarriages, no statistically significant differences with respect to frequencies of allele 2 genotypes IL-1 RA 1/2 (23% TABLE 1 Characteristics of women with idiopathic recurrent miscarriage. Parameters Value TABLE 2 Allele frequencies of IL-1 RA polymorphisms among women with idiopathic recurrent miscarriage and controls. Allele frequency IL-1 RA allele Women with IRM Controls Odds ratio (95% CI) P value a Age at miscarriage evaluation in y, median (range) 31.5 (23 43) No. of miscarriages, median (range) 3.8 (3 9) No. of live births, median (range) 0.3 (0 3) No. of primary aborters (%) 73 No. of secondary aborters (%) ( ) ( ) ( ).6 Note: IRM idiopathic recurrent miscarriage; CI Confidence Interval. a Fisher s exact test. FERTILITY & STERILITY 685

4 vs. 26%, P.2) and IL-1 RA 2/2 (8% vs. 10%, P.1) were observed. DISCUSSION This study demonstrates the allele 2 polymorphism of the IL-1 RA gene to be significantly associated with recurrent idiopathic miscarriage. The data shows that patients with idiopathic recurrent miscarriage have a 13-fold risk of being homozygous at allele 2 for IL-1 RA. This adds further evidence to the concept of an immunologic basis of recurrent idiopathic miscarriage. Familial clustering of recurrent miscarriage has been described, suggesting an inherited component for this condition (29). Skewed inactivation of X chromosome and HLA haplotype sharing have been advocated as etiologic genetic factors of recurrent miscarriage (30, 31). Further evidence of a genetic basis of recurrent miscarriage has been provided by association studies with a variety of genetic markers. In a series of 80 Caucasian women with recurrent miscarriage, Foka et al. showed a significantly higher prevalence of the factor V Leiden G1691A mutation and the prothrombin G20210A mutation compared with a control population (32). Some (33, 34), but not other studies (35, 36), also reported an association between factor V Leiden and recurrent miscarriage. Another candidate gene, angiotensinogen, has been linked to miscarriage in a rodent model (37). The data on IL-1 RA presented in our study add a further component to the multigenetic background that has been established for recurrent miscarriage. Our results are in accordance with previously reported data suggesting a functional role of proinflammatory cytokines in recurrent miscarriage. Murine studies indicate that dominance of TH-1 dependent cytokines, such as IL-1, IL-2, TNF-, and IFN-, is incompatible with successful pregnancy (38). Moreover, injection of TNF- and IL-1 antagonists has been demonstrated to prevent pregnancy loss in the CBA DBA/2 mouse model, in which losses occur at a developmental stage comparable to that seen in clinical miscarriages in humans (39). In a recent report, Jenkins et al. demonstrated elevated serum levels of IFN-gamma and IL-10 among women with recurrent miscarriage (18). Also, women with recurrent miscarriage have been found to exhibit increased IL-12 serum levels. IL-12 is a proinflammatory cytokine, known to promote IFN- production (40). IL-1, produced by monocytes, macrophages, and epithelial cells, induces proliferation and cytokine release of TH-1 cells. In addition, activated TH-1 cells produce IL-1 in an autocrine feedback loop to multiply its effect on induction of inflammatory states (19). The data presented in our study add further evidence to the concept of IL-1 RA as a physiologic mediator of idiopathic recurrent miscarriage. Of note, women who were homozygotes for allele 2 of IL-1 RA (IL-1 RA 2/2 ) demonstrated successful pregnancies, albeit to a lesser extent than wild-type controls. This indicates that IL-1 RA has a functional role but is not necessary for a viable pregnancy. Possible reasons for the reduced penetrance of IL-1 RA 2/2 include stochastic events, modifier genes, and redundant regulatory mechanisms of proinflammatory cytokine release. We acknowledge, however, that the results of an allele association study constitute no proof of an etiologic role of IL-1 RA in idiopathic recurrent miscarriage. It is a further limitation of this study that we cannot specify at what level the presence of functionally impaired IL-1 RA may interfere with maternal immunotolerance of the embryo/fetal allograft. Because suppression of T-cell proliferation in the placenta by indoleaminedioxygenase prevents abortion in an experimental setting (41), we speculate that genetic IL-1 RA deficiency acts primarily on the placental level. Further studies are necessary to clarify whether reduced placental levels of intact IL-1 RA increase exposure of the embryo or fetus to maternal immune response mechanisms. Identification of a link between idiopathic recurrent miscarriage and a specific variant of a gene involved in the regulation of the maternal proinflammatory immune response allows further insight into the natural history of this syndrome and allows identification of susceptible women. Preventive therapeutic strategies have been described for women with idiopathic recurrent miscarriage, such as preconceptual low-dose immunoglobulins or aspirin-cortisone combination therapy (42, 43). Genetic characterization of susceptibility to idiopathic recurrent miscarriage could identify high-risk women who are most likely to profit from preventive therapies. If our data are confirmed in other populations, the functional role of IL-1 RA in idiopathic recurrent miscarriage may lead to new therapeutic strategies, such as recombinant IL-1 RA for women with inherited IL-1 RA deficiency, such as in the case of homozygote carriers of the IL-1 RA allele 2 polymorphism. References 1. American College of Obstetricians and Gynecologists. Early pregnancy loss. ACOG Technical Bulletin No Washington, DC: American College of Obstetricians and Gynecologists, Orgad S, Loewenthal R, Gazit E, Sadetzki S, Novikov I, Carp H. The prognostic value of anti-paternal antibodies and leukocyte immunization on the proportion of live births in couples with consecutive recurrent miscarriages. Hum Reprod 1999;14: Tho PT, Byrd JR, McDonough PG. Etiologies and subsequent reproductive performance of 100 couples with recurrent abortion. Fertil Steril 1979;32: Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials. Br J Obstet Gynaecol 1989;96: Kutteh WH. Recurrent pregnancy loss: an update. Curr Opin Obstet Gynecol 1999;11: Okon MA, Laird SM, Tuckerman EM, Li TC. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function. Fertil Steril 1998;69: Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, et al. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993;60: Witkin SS, Ledger WJ. Antibodies to Chlamydia trachomatis in sera of women with recurrent spontaneous abortions. Am J Obstet Gynecol 1992;167: Simpson JL, Elias S, Meyers CM, Ober C, Martin AO. Translocations 686 Unfried et al. An IL1-RA polymorphism and recurrent miscarriage Vol. 75, No. 4, April 2001

5 are infrequent among couples having repeated spontaneous abortions but no other abnormal pregnancies. Fertil Steril 1989;51: Coulam CB, Clark DA, Collins J, Scott JR, Schlesselman JJ. A worldwide collaborative observational study and metaanalysis on allogenic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol 1994;23: Sugi T, Katsunuma J, Izumi S, McIntyre JA, Makino T. Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses. Fertil Steril 1999;71: Wilson R, Ling H, MacLean MA, Mooney J, Kinnane D, McKillop JH. Thyroid antibody titer and avidity in patients with recurrent miscarriage. Fertil Steril 1999;71: Beer AE. Immunopathologic factors contributing to recurrent spontaneous abortions in humans. Am J Reprod Immunol 1983;4: Raghubathy R, Makhseed M, Azizieh F, Hassan N, Al-Azemi M, Al-Shamali E. Maternal TH1-and TH2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol 1999;196: Szekeres-Bartho J, Wegmann TG. A progesterone-dependent immunomodulatory protein alters the TH1/TH2 balance. J Reprod Immunol 1996;31: Eblen AC, Gercel-Taylor C, Shields LB, Sanfilippo JS, Nakajima ST, Taylor DT. Alterations in humoral immune responses associated with recurrent pregnancy loss. Fertil Steril 2000;2: Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281: Jenkins C, Roberts J, Wilson R, MacLean MA, Shilito J, Walker JJ. Evidence of a TH1 type response associated with recurrent miscarriage. Fertil Steril 2000; 6: Dinarello CA. Biology of interleukin-1. FASEB J 1998;2: Dinarello CA. Inflammatory cytokines: interleukin-1 and tumor necrosis factor as effector molecules in autoimmune diseases. Curr Opin Immunol 1991;3: Bioque G, Crusius JB, Koutroubakis I, Bouma G, Kastense PJ, Meunissen SG, et al. Allelic polymorphism in IL-1 and IL-1 receptor antagonist (IL-1RA) genes in inflammatory bowel disease. Clin Exp Immunol 1995;102: Schrijer HM, Crusius JB, Uitdehaag BM, Garcia Gonzalez MA, Kostense PJ, Polman CH, et al. Association of interleukin-1 beta and interleukin-1 receptor antagonist genes with disease severity in MS. Neurology 1999;52: Santtila S, Savinainen K, Hurme M. Presence of IL-1RA allele 2 is associated with enhanced IL-1 production in vitro. Scand J Immunol 1998;47: Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB. The human IL-1 receptor antagonist gene maps to chromosome 2q14 21 in the region of the IL-1 loci. Genomics 1992;13: Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 1993;91: Jeremias J, Ledger WJ, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol 2000;182: Mansfield JC, Holden H, Tarlow JK, Di Giovine FS, McDowell TL, Wilson AG, et al. Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Gastroenterology 1994;106: Tarlow JK, Clay FE, Cork MJ, Blakemore AI, McDonagh AJ, Messenger AG, et al. Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol 1994;103: Mowbray JF, Underwood J, Gill TJ. Familial recurrent spontaneous abortions. Am J Reprod Immunol 1991;26: Pegoraro E, Whitaker J, Mowery-Rushton P, Surti U, Lanasa M, Hoffmann EP. Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Am J Hum Genet 1997;61: Hedrick PW. HLA-sharing, recurrent spontaneous abortion, and the genetic hypothesis. Genetics 1988;119: Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A, Agarastos T, et al. Factor V Leiden and prothrombin G A mutations, but not methlenetetrahydrofolate reductase C 677T, are associated with recurrent miscarriages. Hum Reprod 2000;15: Souza SS, Ferriani RA, Pontes AG, Zago MA, Franco RF. Factor V Leiden and factor II G20210A mutations in patients with recurrent abortion. Hum Reprod 1999;14: Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999;82: Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999;71: Holmes ZR, Regan L, Chilcott I, Cohen H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol 1999;105: Tempfer CB, Moreno RM, Gregg AR. Genetic control of fertility and embryonic waste in the mouse: a role for angiotensinogen. Biol Reprod 2000;62: Wegmann TG, Lin H, Guilbert L, Mosnman TR. Bidirectional cytokine interaction in maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14: Arck PC, Troutt AB, Clark DA. Soluble receptors neutralizing TNFalpha and IL-1 block stress-triggered murine abortion. Am J Reprod Immunol 1997;37: Wilson R, McInnes I, Leung B, Mc Killop JH, Walker JJ. Altered interleukin 12 and nitric oxide levels in recurrent miscarriage. Eur J Obstet Gynecol Reprod Biol 1997;75: Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AI. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999;189: Stricker RB, Steinleitner A, Bookoff CN, Weckstein LN, Winger EE. Successful treatment of immunologic abortion with low-dose intravenous immunoglobulin. Fertil Steril 2000;73: Retznikoff-Etievant, Cayol V, Zou GM, Abuaf N, Robert A, Johanet C, et al. Habitual abortions in 678 healthy patients: investigation and prevention. Hum Reprod 1999;14: FERTILITY & STERILITY 687

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