Mol. Hum. Reprod. Advance Access originally published online on October 29, 2004
Molecular Human Reproduction 2004 10(12):911-915; doi:10.1093/molehr/gah120
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Polymorphisms of genes involved in innate immunity: association with preterm delivery
1Department of Pediatrics, and 2Obstetrics and Gynecology, University of Luebeck, 3Childrens Hospital auf der Bult, Hannover, 4University Childrens Hospital, Mannheim, 5Childrens Hospital Kassel, 6Childrens Hospital St. Hedwig, Regensburg, 7Childrens Hospital St. Jürgen-Straße, Bremen and 8Childrens Hospital Saarbrücken, Germany
9 To whom correspondence should be addressed at: Department of Paediatrics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Email: goepel{at}paedia.ukl.mu-luebeck.de
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Abstract |
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An altered inflammatory activity due to functionally relevant polymorphisms of the innate immune system may influence pathways leading to labour and, therefore, impact on the frequency of preterm birth. We examined five polymorphisms of the innate immune system in a large cohort of preterm very-low-birth-weight (VLBW, n=909) and term-born infants (n=491) and their mothers (n=747). The primary outcome was preterm versus term birth. Frequencies of polymorphisms in mothers of term-born infants versus mothers of VLBW infants and term infants versus preterm VLBW infants (singletons) are given. Homozygous CD14-159T: 18.5 versus 21.8% (mothers) and 19.6 versus 21.2% (infants). Homozygous interleukin IL-6-174G: 28.8 versus 38% (P=0.018, mothers) and 30 versus 32.7% (infants). Homozygous or heterozygous nuclear oligomerization domain NOD2-3020insC: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Heterozygous or homozygous toll-like-receptor TLR2-Arg753Gln: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Homozygous or heterozygous TLR4-896G: 8.1 versus 11.5% (mothers) and 11.6 versus 10.5% (infants). Although the homozygous maternal IL-6-174G genotype was found to be independently associated with preterm delivery in multivariate regression analysis, the incidence of intrauterine infection was not significantly increased in mothers of preterm VLBW-infants, carrying this or other polymorphisms of the innate immune system. The overall influence of the investigated polymorphisms on the development of preterm delivery seems moderate, since only the maternal IL6-174G genotype was associated with preterm birth and none of the polymorphisms were associated with intrauterine infection as the cause of preterm birth.
Key words: innate immunity/interleukin/intrauterine infection/preterm delivery/toll-like receptor
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Introduction |
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Preterm birth is still a frequent problem in neonatal care with a prevalence up to 11% (Goldenberg and Rouse, 1998
; Stoll et al., 2002a,b). Although the pathophysiology of preterm delivery is known to be multifactorial, the inflammatory response of the placental tissue to ascending or intrinsic infections is considered to play a crucial role in about 80% of all premature births (Gomez et al., 1995; Goldenberg and Rouse, 1998). Recent investigations on innate immunity have triggered the identification of specific mutations, which are associated with an altered expression of immunological factors. Increased levels of inflammatory activity may stimulate pathways leading to labour and, therefore, cause a higher incidence of preterm delivery.
The inflammatory immune reponse is mainly initiated by the recognition of bacterial motifs, such as lipopolysaccharide (LPS), by means of the innate immune system (Cohen, 2002). Recent advances in the understanding of molecular events involved in inflammation have pointed to the functional relevance of variant alleles of innate immunity genes.
The opsonic co-receptor CD14 is essential to mediate the LPS activation of monocytes (Cohen, 2002). In adults, the homozygous 159T mutation of the CD14 gene (CD14-159T) was demonstrated to result in a high mortality rate in sepsis (Gibot et al., 2002). The toll-like receptor (TLR) proteins TLR2 and TLR4 were also demonstrated to be major LPS-recognition receptors (Hallman et al., 2001). The 896G mutation of the toll-like-receptor-4 (TLR4-896G) leads to a reduced nuclear-factor-kappaB (NF-
B) activation after LPS stimulation in vitro, and to airway hyporesponsiveness after LPS inhalation in vivo (Arbour et al., 2000). Furthermore, an association of this mutation with a high frequency of septic shock was found in adults (Lorenz et al., 2002a). Recently, an association between the 896G mutation of the TLR4-896G in neonates and preterm birth has been described (Lorenz et al., 2002b). The TLR2-Arg753Gln mutation was reported to predispose adult individuals to life-threatening staphylococcal infections (Lorenz et al., 2000). Furthermore, the intracellular proteins NOD1 and NOD2 (for nucleotide-binding oligomerization domain) were described to have the ability to bind and to confer responsiveness to LPS. Genotypic variations such as the NOD2-3020insC mutation are associated with reduced NF-B response after stimulation with several Gram-negative bacteria in vitro (Ogura et al., 2001) and, in addition to that, linked to Crohn's disease (Hampe et al., 2001; Hugot et al., 2001; Ogura et al., 2001). The inflammatory response is further characterized by increased secretion of cytokines, such as interleukin (IL)-6. The IL-6-174 promoter genotype was demonstrated to determine different levels of IL-6 response to stressful stimuli between individuals, whereas the C-allele was associated with lower levels of plasma-IL-6 in individuals (Fishman et al., 1998).
The aim of the study was to determine the predictive value of variant alleles of the innate immune system as genetic markers for preterm delivery.
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Materials and methods |
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Study population
We studied the influence of gene polymorphisms involved in innate immunity on preterm delivery in a large cohort of infants [n=909 preterm very-low-birth-weight (VLBW) infants, n=491 singleton term infants as control group] and their mothers (n=466 mothers of preterm VLBW infants, n=281 mothers of term-born infants). The primary outcome of this study was preterm versus term birth. Our study population was enrolled in a retrospective study (1992–2000, University of Lübeck Medical School) and an open multicentre study concerning the impact of genetic factors on preterm delivery and the clinical course of preterm VLBW infants from January 2000 to October 2003. The cause for preterm delivery [pre-eclampsia, intrauterine infection (elevated signs of infection, e.g. white blood cell count, C-reactive protein), placental abruption, pathological cardiotocography (CTG), premature labour and others] was defined by the attending physician. Since polymorphism frequencies differ widely between populations (Hassan et al., 2003
; Simhan et al., 2003), we decided to exclude infants of African and far-Eastern descendants (n=18 preterm VLBW, n=1 singleton term infant, n=12 mothers of preterm VLBW infants, n=1 mother of a term infant). Clinical data of all infants and their mothers were documented and coded before mutation analysis.
Genotyping
DNA samples were extracted from dried blood spots (retrospective study) and from buccal swabs (prospective study). DNA was extracted with a commercially available kit (Qiagen, Hilden, Germany). All polymorphisms were detected by PCR and restriction enzyme digestion. Primer and DNA sequences were depicted from previously published reports (Fishman et al., 1998; Baldini et al., 1999; Unkelbach et al., 1999; Lorenz et al., 2000; Hampe et al., 2001; Gibot et al., 2002; Lorenz et al., 2002b). Primer pairs for detection of the CD14-159T mutation were 5'-GTG CCA ACA GAT GAG GTT CAC-3' and 5'-GCC TCT GAC AGT TTA TGT AAT C-3' (AvaII-digest), for the TLR2-Arg753Gln polymorphism 5'-TAT GGT CCA GGA GCT GGA GA-3' and 5'-TGA CAT AAA GAT CCC AAC TAG ACA A-3' (PstI-digest), for the TLR4-896G mutation 5'-ATA CTT AGA CTA CTA CCT CCA-3' and 5'-CTT TGT TGG AAG TGA AAG TAA GCC-3' (NcoI-digest) for the NOD2-3020insC-mutation 5'-CTG AGC CTT TGT TGA TGA GC-3' and 5'-TCT TCA ACC ACA TCC CCA TT-3' (NlaIV-digest) and 5'-TGA CTT CGA CTT TAC TCT TGT-3' and 5'-CTG ATT GGA AAC CTT ATT AAG-3' (NlaIII-digest) for the IL-6-174 mutation.
The expected carrier frequencies for Caucasian populations for the homozygous CD14-159T mutation, the homozygous or heterozyguous TLR2-Arg753Gln polymorphism, TLR4-896G and NOD2-3020insC mutations and the homozygous IL-6-174G promoter polymorphism were 20% (Baldini et al., 1999), 3% (Lorenz et al., 2000), 12% (Lorenz et al., 2002a), 8% (Ogura et al., 2001) and 37% (Fishman et al., 1998; Kilpinen et al., 2001), respectively.
Based on these expected frequencies, an alpha error <0.05 (two-sided) and a power of 0.8, our sample size (term-born singletons, n=492 versus preterm VLBW singletons, n=606) would be sufficient to detect differences of carrier frequencies between cases and controls from 4% (TLR2-Arg753Gln) to 8% (IL-6-174).
Statistical analysis
Data analysis was performed using the Statistics Package for Social Sciences 9.0 data analysis package (Munich, Germany). Hypotheses were evaluated with Fisher's exact test (two-sided) and multivariate logistic regression models. A P-value of <0.05 was considered as statistically significant.
Ethics
All parts of the study were approved by the local committee on research on human subjects of the Medical University of Lübeck.
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Results |
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The clinical data of mothers and infants of the prospective cohort are given in Table I. Preterm VLBW infants enrolled in the retrospective study and the prospective study did not differ significantly in birth weight, gender and frequency of multiple birth (data not shown). PCR was not successful in two infants of the retrospective group. Distribution of polymorphisms in preterm VLBW versus term infants and their mothers were in Hardy–Weinberg equilibrium. Frequencies are given in Table IIa. Only the maternal IL-6-174 GG genotype was more frequent in mothers of VLBW infants (38 versus 28.8%; P=0.018). In addition to that, mothers of preterm singleton VLBW infants were found to have less expression of the IL-6-174C allele (36.1 versus 41.7%; P=0.02) than mothers of term infants (Table IIb). As preterm delivery due to pre-eclampsia and spontaneous preterm delivery may arise from different underlying mechanisms and associated genotypes, we performed an additional analysis in which mothers with pre-eclampsia as an isolated pathogenic factor (n=35) and mothers with unknown cause of preterm delivery were excluded (n=16). The estimated genotype frequencies in the remaining group of VLBW mothers (n=314) versus mothers of term newborns (n=281) were as follows: IL-6-174GG genotype (39.2 versus 28.8%; P=0.009), CD14-159T mutation (21.7 versus 18.5%; P=0.2), the TLR2-Arg753Gln polymorphism (6.3 versus 6.1%; P=1.0), TLR4-896G mutation (11.1 versus 8.1%; P=0.14) and NOD2-3020insC mutation (6.1 versus 6.9%; P=0.73). When this group was analysed for the genotypic frequencies of infants, no significant differences were noted between preterm VLBW versus term infants (data not shown).
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To rule out possible confounding, we did a multivariate logistic regression analysis including previous premature delivery <37 gestational weeks and all gene polymorphisms studied as independent variables and premature delivery as a dependent variable (Figure 1). After stepwise exclusion of non-significant independent variables, only previous premature delivery <37 gestational weeks (OR 5.42, 95% confidence interval (CI) 2.0–14.6; P=0.001) and the homozygous carrier status of the IL6-174G mutation (OR 1.48, 95% CI 1.0–2.2; P=0.042) were significant predictors of preterm delivery.
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Causes of preterm delivery in the whole group were intrauterine infection (20.6%), pre-eclampsia (20.0%), placental abruption (9.0%), pathological CTG (26.0%), premature labour (22.4%) and other causes (2.0%). The frequency of intrauterine infection did not differ between mothers with or without polymorphisms of innate immunity genes. In line with this, the frequencies of intrauterine infection were neither significantly associated with the homozygous IL-6-174GG genotype (17.7 versus 22.5%; P=0.26) nor the CD14-159T mutation (20.5 versus 20.7%; P=1.0), nor the homozygous or heterozygous TLR2-Arg753Gln polymorphism (23.1 versus 20.5%; P=0.8), TLR4-896G mutation (24.4 versus 20.2%; P=0.18) and NOD2-3020insC mutation (32.0 versus 19.9%; P=0.19).
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Discussion |
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The aim of our study was to investigate the impact of gene polymorphisms involved in the innate immune system on preterm delivery in a large cohort of preterm VLBW and their mothers. Although this study exclusively investigated point mutations, which were found to have a functional relevance on host immune response (Arbour et al., 2000
; Lorenz et al., 2000; Ogura et al., 2001; Gibot et al., 2002; Lorenz et al., 2002a), and we enrolled more than 2100 patients and controls, only a previous pregnancy which terminated before gestational week 37 and the homozygous IL-6-174G promoter genotype of the mother, but not of the infant, were associated with preterm delivery. The IL-6-174C allele was less expressed in mothers of VLBW infants, thus confirming the findings of Simhan et al. (2003) in a study population consisting of 51 mothers with spontaneous preterm delivery and 156 controls. When mothers with indicated preterm delivery (e.g. pre-eclampsia) were excluded from analysis, the association between the maternal IL-6-174G promoter genotype and preterm delivery was even more significant.
Furthermore, we did not observe a significant increase in the rate of intrauterine infections in maternal carriers of any of the mutations. Thus, we could not confirm the findings of various epidemiological studies, which reported significantly higher frequencies of gene mutations of the innate immune system in adult patients with severe infections or sepsis (Inohara et al., 2001; Gibot et al., 2002; Lorenz et al., 2002a; Schluter et al., 2002). Intrauterine infection and neonatal septicaemia are regarded as disease states with different pathogenesis, and therefore the impact of the genetics of signal molecules involved in early recognition of bacteria may be variable. Previously, Harding et al. (2003) and our study group noted a significant association of the homozygous IL-6-174G/G promoter genotype in preterm infants with septicaemia (Ahrens et al., 2004). IL-6 is a pleiotropic cytokine with not only proinflammatory but also anti-inflammatory and immunosuppressive properties (Tilg et al., 1997; Xing et al., 1998). Genetic variations of the IL-6 gene may have a distinct role in certain disease states. Among term infants, raised peripartum IL-6 levels and endotoxin-stimulated monocyte IL-6 production were found to be associated with the IL-6-174C allele in newborns (Kilpinen et al., 2001). If lower IL-6 levels are in part responsible for a state of relative immunocompromise in neonates, the observed association of the IL-6-174G allele, and particularly the G/G genotype, with elevated risk of bacterial infection in preterm infants is plausible.
In adult populations, however, allele frequencies of the IL-6-174 promoter genotype did not differ significantly between patients with or without sepsis and median systemic IL-6 levels were not associated with the genotype (Schluter et al., 2002). These differences compared to investigations in neonates may be explained by various gene–environment interactions in adults, and the range of underlying pathologies leading to bacterial infection. While studies concerning the effect of different IL-6-174 promoter genotypes on IL-6 plasma and C-reactive protein levels gave conflicting results demonstrating no or only moderate effects (Margaglione et al., 2001; Heesen et al., 2002), Fishman et al. (1998) found significantly lower IL-6 plasma levels in healthy adults carrying the IL-6-174C allele. The IL-6-174G/G genotype was associated with high levels of IL-6 expression. Our findings that the maternal IL-6-174G/G genotype is associated with preterm delivery, but not necessarily intrauterine infection, points to the distinct role of IL-6 in a complex regulatory network involved in the placental development and parturition. In line with this, the relative level of inflammatory activity seems to be more important for the IL-6 involvement than the level of exposure to infectious pathogens. It has been previously shown, that IL-6 is linked with the inflammatory events precipitating parturition (Bowen et al., 2002). Moreover, IL-6 is likely to play other roles in placental development, in addition to immunologic functions, such as decidualization of endometric stroma cells, crosstalk at the feto–maternal interface leading to expulsion of the fetus by uterus contractions and membrane rupture, and dilation of the cervix (Dealtry et al., 2000; Bowen et al., 2002).
Potentially, IL-6 may also contribute to preterm delivery by influencing prothrombotic events in placental vessels. This hypothesis is supported by the findings of Greisenegger et al. (2003) who described the IL-6-174G/G genotype to be associated with severe stroke in young patients with acute cerebrovascular events.
In addition to that, recent data in the murine model suggest that IL-6 not only produced by immunocompetent cells, but also by trophoblasts and decidua cells, is directly involved in the pathology of abortion (Zenclussen et al., 2003). In the search for genetic risk factors for idiopathic recurrent miscarriage (IRM), two case-control studies so far reported no association of the maternal IL-6-174 promoter genotype with IRM (Daher et al., 2003; Unfried et al., 2003).
In contrast to Lorenz et al. (2002b), we could not find a significant association between the fetal TLR4-896G mutation and preterm birth. This discrepancy may be explained by differences in the study population (Finnish cohort versus German cohort) and characteristics of preterm infants, since our cohort included preterm VLBW infants with a mean gestational age of 28.3 weeks compared to 33.0 weeks in the Finnish cohort. Furthermore, Erridge et al. (2003) recently challenged the work on the significance of the TLR4-896G mutation by demonstrating that monocytes from heterozygous individuals exhibit no deficit in recognition of LPS.
In conclusion, our data and the current literature suggest that polymorphisms of the innate immune system, despite their reported functional relevance on host immune response, have a much lower impact on subsequent preterm delivery than known risk factors like previous preterm birth.
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Other investigators of the Genetic Factors in Neonatology Study Group: B. Köhler (Marburg), J. Seidenberg (Oldenburg), R. Jensen (Heide).
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Acknowledgements |
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We thank Anja Sewe, Lynn Ellenberg and Sabine Ziesenitz for excellent laboratory assistance, Birgit Roenspiess for skillful data collection, all doctors and nurses of the participating hospitals and especially all infants and their parents for their support. This work was supported by the Deutsche Forschungsgemeinschaft, Grant No.: Go 955/1-1-3, and by the University of Lübeck, Grant No.: FSRM 3.2.2.
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Submitted on June 15, 2004; resubmitted on September 24, 2004; accepted on October 3, 2004.
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