Role of Single Nucleotide Polymorphisms of Cytokine Genes in Spontaneous Preterm Delivery

doi:10.1016/j.humimm.2006.08.291

Human Immunology

Volume 67, Issue 11, November 2006, Pages 915-923

https://doi.org/10.1016/j.humimm.2006.08.291 Get rights and content

Abstract

Intra-amniotic infections are implicated in spontaneous preterm delivery (PTD). Certain genetic polymorphisms are associated with increased production of proinflammatory and/or decreased production of anti-inflammatory cytokines, thereby possibly promoting PTD. We determined the relationship between maternal and fetal cytokine gene polymorphisms with occurrence and severity of spontaneous PTD (PTD after spontaneous-onset preterm labor and/or preterm prelabor rupture of membranes) and their association with intrauterine inflammation and infection. DNA from buccal brushings of 80 preterm (gestation < 35 weeks) and 80 matched term mother-infant pairs was assayed for tumor necrosis factor α (TNF-α [−308G/A]), interferon-γ (IFN-γ [+874A/T]), interleukin-6 (IL-6 [−174C/G]), interleukin-10 (IL-10 [−1082G/A, −819C/T, −592C/A]), and transforming growth factor β₁ (TGF-β₁ [T/Ccodon10,G/Ccodon25]) by using polymerase chain reaction (PCR) with sequence-specific primers. The presence of histologic chorioamnionitis was determined for PTDs. Conditioned on maternal IFN-γ genotypes, fetal high IFN-γ producing allele (IFN-γ[+874T]) was associated with spontaneous PTD (odds ratio = 2.3 [1.2–4.4]). Among preterm deliveries, maternal low TGF-β₁ (TGF-β₁ [codon10C]) producing genotypes correlated negatively with gestation. Fetal TNF-α (−308G) was significantly associated with histologic chorioamnionitis. Underlying genitourinary infections and/or inflammation were significantly associated with maternal and fetal IL-6 (−174G), fetal TNF-α (−308GG), and fetal IL-10 (−1082A). We conclude that certain fetal and maternal cytokine gene polymorphisms may be associated with occurrence and/or severity of spontaneous PTD and with intrauterine inflammation and infection.

Introduction

Preterm delivery (PTD) continues to be an ongoing problem in perinatal medicine. Approximately 12% of all deliveries in the United States are preterm, accounting for 70% of perinatal mortality and nearly half of long-term neurologic morbidity [1]. Intra-amniotic infection, which is often subacute, appears to play a central role in the pathogenesis of spontaneous PTD and is particularly prevalent in very early PTDs [1, 2, 3]. Infection triggers an inflammatory response in maternal and fetal tissues, which is mediated through the production of proinflammatory cytokines. This in turns leads to prostaglandin production, increased myometrial contractility, fetal membrane rupture, cervical ripening and change, and ultimately to PTD [1, 3, 4, 5, 6, 7]. The intensity of the maternal and fetal inflammatory response and the resulting progression to PTD might thus be related to the overproduction of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interferon-γ (IFN-γ), or to the underproduction of antiinflammatory cytokines, such as interleukin 10 (IL-10) and transforming growth factor β₁ (TGF-β₁) [3, 5, 8, 9, 10, 11].

The expression of cytokines in response to various stimuli is under genetic control. Single nucleotide polymorphisms (SNPs) have been described for many human cytokine genes. These polymorphisms are frequently located within the regulatory region of cytokine genes and represent common allelic variations, some of which have been found to affect the transcriptional activation of the gene. Such functional polymorphisms can increase or decrease the production of the corresponding cytokine protein in response to various stimuli and thus affect illness severity during certain infectious and autoimmune diseases and organ rejection after transplantation [12, 13, 14, 15]. For example, the substitution of adenine for guanine within the promoter of the gene for TNF-α at position −308 relative to the transcription start site has been associated with enhanced TNF-α production and with increased susceptibility to and severity of septic shock [12, 13]. In the presence of an intrauterine infection, interindividual differences in concentrations of inflammatory cytokines within the feto-maternal unit may thus, in part, be due to maternal and fetal carriage of certain cytokine gene polymorphisms. Individuals who are genetically predisposed to react upon microbial stimulation with an intense inflammatory response might therefore be at increased risk for the progression to preterm labor and delivery [16, 17, 18].

In a matched case-control study among mothers and infants delivered preterm versus at term, we examined the frequency distributions of several cytokine gene polymorphisms of proinflammatory and antiinflammatory cytokines and assessed their relationship to the severity of spontaneous PTD and the presence of intrauterine inflammation and/or infection. The SNPs included in this study were chosen because they are known to influence the gene’s function 12, 13, 14, 19, 20, 21), and their corresponding proinflammatory and antiinflammatory cytokines have been found to play a key role in the pathologic inflammation leading to preterm labor and delivery [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11].

Section snippets

Subjects

This study was approved by the Institutional Review Board of Magee-Womens Hospital in Pittsburgh, PA, and written informed consent was obtained from all mothers prior to enrollment. Eighty mother and infant pairs with spontaneous singleton PTD before 35 completed weeks of gestation were recruited soon after birth from consecutive eligible deliveries (n = 76) or transfers (n = 4) to Magee-Womens Hospital. Spontaneous delivery was defined as delivery following spontaneous-onset labor and/or

Results

Among the preterm group, 49% of the pregnant women experienced preterm labor alone, 41% experienced preterm labor and preterm prelabor rupture of membranes, and 10% experienced preterm prelabor rupture of membranes without spontaneous onset labor. The demographic and clinical characteristics of cases and controls are found in Table 1. Whereas sociodemographic variables were equally distributed among the study groups, a significantly higher percentage of case mothers suffered from medical

Discussion

The genotype and haplotype frequencies among our control patients are comparable to those reported by others for predominantly Caucasian populations [15, 25, 26]. Several polymorphisms of cytokine genes have previously been associated with spontaneous preterm delivery, but the findings were not consistent. Roberts et al. examined inner-city African-American women and presented a relationship of the TNF-α (−308A) allele and PTD after preterm prelabor rupture of membranes, but not with intact

Acknowledgments

We thank Jordan Trecki, Allegheny-Singer Research Institute, for performing the DNA extractions, and Jeanette Dunn, Department of Pathology, Magee-Womens Hospital, for performing the placental pathology examinations.

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The determinant role of IL-6 in the establishment of inflammation leading to spontaneous preterm birth
2021, Cytokine and Growth Factor Reviews
Citation Excerpt :
It is located in a key promoter region controlling the induction of cytokine transcription. Several studies have associated -174 GG/GC genotype, resulting in increased IL-6 production, as a major inducer of inflammation underlying PTB [37–39]. The CC genotype, which results in decreased IL-6 production, is thought to have a protective effect [37,40–42].
Preterm birth (PTB) and its consequences are a major public health concern as preterm delivery is the main cause of mortality and morbidity at birth. There are many causes of PTB, but inflammation is undeniably associated with the process of premature childbirth and fetal injury. At present, treatments clinically available mostly involve attempt to arrest contractions (tocolytics) but do not directly address upstream maternal inflammation on development of the fetus. One of the possible solutions may lie in the modulation of inflammatory mediators. Of the many pro-inflammatory cytokines involved in the induction of PTB, IL-6 stands out for its pleiotropic effects and its involvement in both acute and chronic inflammation. Here, we provide a detailed review of the effects of IL-6 on the timing of childbirth, its occurrence during PTB and its indissociable roles with associated fetal tissue damage.
IL-6: An endogenous activator of MMP-9 in preterm birth
2020, Journal of Reproductive Immunology
Preterm birth or PTB (<37 weeks) is a heterogeneous phenotype with numerous biological pathways. The lack of explanation due to complex pathways, inconsistent observations indicates the need for employing the role of genetic determinants to anticipate the danger of PTB. In this present study, we investigated the possible gene-gene interaction of five SNPs with PTB and its association with total MMP-9 levels. A total of 510 recruitments (250 terms and preterm each) were made and were genotyped by Restriction Fragment length polymorphism (RFLP). Generalized Multifactor Dimensionality Reduction (GMDR) method was carried out for determining gene-gene interaction. ANOVA and t-test were used to identify the association of IL-6 polymorphism with PTB alone and correspondingly with PTB and low birth weight infants (i.e. < 2500 kg). The combination of IL-6 and MMP-9 and MMP-1, MMP-8 and MMP-9 polymorphism was selected through GMDR analysis concerning mothers with preterm and term birth (accuracy 0.5921 and 0.8030 with Cross-Validation Consistency (CVC) 10/10 respectively). Increased expression of MMP-9 was reported in cases in those mothers carrying IL-6 G allele, which was profoundly associated with PTB independently. IL-6 polymorphisms showed synergistic effects in terms of increased total MMP-9 levels in the present study.
Spontaneous preterm birth: advances toward the discovery of genetic predisposition
2018, American Journal of Obstetrics and Gynecology
Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (eg, CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (eg, DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (ie, intraamniotic infection) or “danger signals” (alarmins) released during cellular stress or necrosis (ie, sterile intraamniotic inflammation). These findings support the notion that preterm birth has a polygenic basis that involves rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the whole exome sequencing-identified genes and other inflammatory conditions associated with preterm birth, such as periodontal disease and inflammatory bowel disease, was observed, which suggests a shared genetic substrate for these conditions. We propose that whole exome sequencing, as well as whole genome sequencing, is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous preterm birth, at least in the context of pathologic inflammation. The identification of genes that contribute to preterm birth by whole exome sequencing, or whole genome sequencing, promises to yield valuable population-specific biomarkers to identify the risk for spontaneous preterm birth and potential strategies to mitigate such a risk.
Genetics, hormonal influences, and preterm birth
2017, Seminars in Perinatology
Prematurity is a devastating disease with high neonatal morbidity and mortality based on gestational age at birth. Genetic and hormonal signals impact directly on the maternal predisposition to preterm birth or sudden onset of myometrial contractility. Candidate gene or genome-wide approaches are beginning to identify potential variants for women at risk for premature delivery or increased responsiveness to hormonal signals including progesterone. However, a majority of these studies have not yielded definitive results to allow for at this stage for development of personalized therapy.
Association of -308G/A TNF-α gene polymorphism and spontaneous preterm birth in Acehnese ethnic group, Indonesia: This polymorphism is not associated with preterm birth
2016, Egyptian Journal of Medical Human Genetics
Single nucleotide polymorphism (SNP) within tumor necrosis factor alpha (TNF-α) gene promoter (−308G/A TNFA) is associated with higher gene expression. The role of this SNP as a risk factor for spontaneous preterm birth has been assessed in some regions and the findings were significantly different between race and ethnic groups.
To provide the scientific evidence whether allele A within SNP −308G/A TNFA promoter is a risk factor for spontaneous preterm birth among Acehnese ethnic or not.
In this case–control study, the genotypes of SNP −308G/A TNFA among 40 patients with spontaneous preterm birth and 40 patients with term birth were determined by real-time polymerase chain reaction (RT-PCR). The concentrations of TNF-α from blood were measured by enzyme-linked immunosorbent assay (ELISA). The differences in genotype distributions, dominant and recessive models, and allele frequencies between case and control groups were analyzed with Chi-squared test. Deviation of genotype frequencies from the Hardy–Weinberg equilibrium (HWE) was assessed by Fisher’s exact test.
This study found that the concentration of TNF-α between preterm and control groups was not statistically different, 5.5 ± 2.9 mg/dL vs. 10.1 ± 17.9 mg/dL, p = 0.112. The level of TNF-α had no strong association with either genotype distribution or allele frequency of SNP −308G/A TNFA. Furthermore, there was no association between mutant genotypes and spontaneous preterm birth (OR: 0.32; 95%CI: 0.08–1.33, p = 0.096) and between mutant allele and spontaneous preterm birth (OR: 0.35; 95%CI: 0.09–1.37, p = 0.105).
SNP −308G/A TNFA is not associated with spontaneous preterm birth in Acehnese ethnic group.
Association between maternal tumor necrosis factor-α G308A polymorphism and interferon-γ A874T polymorphism and risk of preterm birth: A meta-analysis
2015, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
The publication year of involved studies ranged from 1999 to 2013. There were nineteen studies published in English [14,18–28,30–32,34–37] and two in Chinese [29,33]. Ethnic groups among these studies were following: seven with 941 cases and 2353 controls were Caucasians [18,20,21,25,28,30,35], four with 274 cases and 317 controls were Asians [19,29,33,37], three with 327 cases and 599 controls were Americans [23,24,32], one with 27 cases and 237 controls were Africans [31], and six with 534 cases and 1564 controls were mixed [14,22,26,27,34,36].
This article was undertaken to investigate the association between tumor necrosis factor-α (TNF-α) G308A polymorphism and interferon-γ (INF-γ) A874T polymorphism and risk of preterm birth (PTB) by performing a meta-analysis of available studies.
Articles were chosen based on PubMed, EMBASE, Web of science, and China Biology Medicine (CBM) databases with no language restriction from their inceptions to 1 March, 2014. Specific inclusion criteria were used to evaluate articles. Meta-analysis was performed by using a random or fixed effect model with STATA 11.0 software. We estimated the summary odds ratios (ORs) with its corresponding 95% confidence interval (95%CI) to assess the association.
21 eligible case–control studies with a total of 2103 cases and 5070 controls were finally included into this meta-analysis. Pooled analysis showed that A allele of TNF-α G308A was not associated with increased PTB risk (OR = 0.84, 95%CI: 0.65–1.07, p = 0.167 for G vs. A). Stratifying analysis for ethnicity and different definition of PTB also indicated that A allele was not associated with increased PTB risk. However, the meta-analysis showed that INF-γ A874T polymorphism was associated with the increased risk of PTB (OR = 1.14, 95%CI: 1.11–1.73, p = 0.004 for A vs. T). Stratifying analysis was not performed due to the small sample size.
TNF-α G308A polymorphism was not associated with an increased risk of PTB, but INF-γ A874T polymorphism may contribute to increasing susceptibility to PTB. Detection of polymorphism of INF-γ A874T might be a promising biomarker for the diagnosis and prognosis of preterm delivery.

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Role of Single Nucleotide Polymorphisms of Cytokine Genes in Spontaneous Preterm Delivery

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgments

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Immunol Today

Am J Obstet Gynecol

Obstet Gynecol

Hum Immunol

Am J Obstet Gynecol

Am J Obstet Gynecol

J Reprod Immunol

Am J Obstet Gynecol

Am J Obstet Gynecol

Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol