Mol. Hum. Reprod. Advance Access originally published online on January 12, 2009
Molecular Human Reproduction 2009 15(2):121-130; doi:10.1093/molehr/gan078
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Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population
1Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan 2Department of Epidemiology, National Institute of Public Health, Wako 351-0197, Japan 3Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan 4Department of Heath Science, Asahikawa Medical College, Asahikawa 078-8510, Japan
5 Correspondence address. Tel: +81-48-458-6115; Fax: +81-48-469-2677; E-mail: sata{at}niph.go.jp
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Abstract |
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Pregnancy and parturition involve a complex and poorly understood molecular and biological interplay between mother and fetus. Inflammatory cytokines have been reported to be associated with fetal growth and parturition. The aim of this study was to examine whether common proinflammatory cytokine polymorphisms are associated with preterm birth (PTB), low birthweight or intrauterine growth restriction in a Japanese population. We assessed a consecutive series of 414 women who had singleton deliveries in Sapporo, Japan between 2001 and 2005. Genotyping of IL1A –889C/T, +4845G/T (A114S), IL1B –511C/T, –31C/T, IL2 –384T/G and IL6 –634C/G polymorphisms was determined by an allelic discrimination assay. The risk of PTB significantly increased in women carrying the IL1A –889T allele (CC genotype [reference]; CT genotype, odds ratios (OR): 2.5; 95% confidence intervals (95% CI): 1.4–4.8; CT+TT genotypes [dominant genotype model], OR: 2.5, 95% CI: 1.3–4.6). Similarly, the risk of PTB significantly increased in women carrying the IL1A +4845T allele (GG genotype [reference]; GT genotype, OR: 2.4, 95% CI: 1.3–4.4; GT+TT genotypes [dominant genotype model], OR: 2.3, 95% CI: 1.2–4.2). The frequency of the IL1A TT haplotype in mothers with PTB was significantly higher than in mothers who had a term birth (P < 0.001), whereas the frequency of the IL1A CG haplotype in mothers who had a PTB was significantly lower (P < 0.001). Our findings suggest that the polymorphisms and haplotypes in the IL1A gene are associated with PTB in Japanese women.
Key words: cytokines/growth factors/gene mutations/haplotype/preterm birth/low birthweight
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Introduction |
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Preterm birth (PTB), a birth at fewer than 37 weeks of gestation, is a major public health concern because of its high prevalence, associated mortality and morbidity, and the expense of both hospitalization and risk of long-term disability (Goldenberg et al., 2000; Crider et al., 2005). PTB occurs in 5–10% of births and is associated with 70–80% of neonatal mortality (Goldenberg et al., 2000). Low birthweight (LBW), a birthweight <2500 g, does not always accompany PTB, but is also associated with increased neonatal morbidity and mortality (McCormick, 1985; Henriksen, 1999).
Over the last decade, it has become increasing apparent that the cause of PTB is multi-factorial and involves both genetic and environmental factors (Santtila et al., 1998; Dominici et al., 2002; Genc et al., 2002; Annells et al., 2004; Moore et al., 2004; Engel et al., 2005; Edwards et al., 2006; Pennell et al., 2007). Family, twins and trans-generational studies have provided evidence that PTB is heritable in some cases (Porter et al., 1997; Clausson et al., 2000; Treloar et al., 2000; Ward et al., 2005). The genes involved in inflammatory processes and the immune system may be one of the most likely targets in the etiology of PTB (Romero et al., 1989a, b; Dinarello, 1991; Hillier et al., 1993; Greig et al., 1997; Santtila et al., 1998; Dominici et al., 2002; Annells et al., 2004; Moore et al., 2004; Crider et al., 2005; Engel et al., 2005; Edwards et al., 2006).
Although parturition involves a complex and poorly understood molecular and biological interplay between the mother and fetus (Crider et al., 2005), there is increasing evidence that infection and the inflammatory response contribute to the etiology of PTB (Goldenberg et al., 2000). Genetic susceptibility factors in immune response genes have been investigated, particularly cytokine polymorphisms which are known to be proinflammatory. Cytokines, such as interleukin (IL)-1 (Romero et al., 1989a; Hillier et al., 1993) and IL-6 (Greig et al., 1997), are responsible for the onset of premature labor and parturition. The IL-1 family consists of three subtypes (gene symbols are in parentheses): IL-1
(IL1A), IL-1β (IL1B) and the specific receptor antagonist, IL-1Ra (IL1RN). The two forms of IL-1, and β, are products of distinct genes and thus have different amino acid sequences; however, they have similar three-dimensional structures, interact with similar receptors and share biological activities (Dinarello, 1991). IL-1 and IL-1β stimulate prostaglandin E2 synthesis by the amnion (Romero et al., 1989b). Single-nucleotide polymorphisms (SNPs) include –889C/T in the transcriptional regulatory region and +4845G/T (A114S) in the coding region of IL1A, and –511C/T and –31C/T in the transcriptional regulatory region of IL1B. Evidence suggests that to a certain extent these polymorphisms cause functional changes. The IL1A –889TT genotype significantly increases the transcriptional activity of IL1A compared with the –889CC genotype (Dominici et al., 2002). Peripheral blood mononuclear cells with the IL1B –511T genotype tend to produce slightly higher IL-1β levels than peripheral blood mononuclear cells with the IL1B –511C genotype (Santtila et al., 1998). And recently, it was reported that SNPs in the IL1B promoter region, containing –511C/T and –31C/T polymorphisms, affect transcription according to haplotype context (Chen et al., 2006).
The IL1A and IL1B polymorphisms are associated with inflammatory diseases, such as periodontal and cardiovascular diseases (Kornman et al., 1997; Kornman and Duff, 2001). These polymorphisms may also influence the onset of premature labor. One study has reported that the fetal IL1B+3953 polymorphism is associated with PTB in the African American population (Genc et al., 2002). However, no studies have detected significant associations between maternal IL1A or IL1B polymorphisms and PTB (Annells et al., 2004; Moore et al., 2004; Engel et al., 2005; Edwards et al., 2006).
We examined the relationships of common polymorphisms in proinflammatory cytokines with PTB and LBW in a cohort of women enrolled in the present study. In this report, we describe the relationship between six polymorphisms in proinflammatory cytokine genes (i.e. IL1A, IL1B, IL2 and IL6) and PTB and LBW. Thus, the aim of the present study was to elucidate the association of proinflammatory cytokine polymorphisms with PTB, LBW and intrauterine growth restriction (IUGR) in a Japanese population.
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Subjects
This birth cohort study was performed in the city of Sapporo, Japan, as described in detail previously (Sata et al., 2006). We recruited the women during scheduled appointments at the Hokkaido University Hospital, a tertiary hospital in the region, for a medical examination one month after delivery between November 2001 and April 2005. A consecutive series of 466 women who had singleton deliveries were studied. There were 52 women who had autoimmune disease, anti-phospholipid syndrome, congenital thrombophilia, gestational diabetes mellitus or who delivered malformed infants in the index pregnancies, and were therefore excluded from the study. Altogether, 414 eligible women, 18–44 years of age, were analyzed in the present study. All the women were residents of Sapporo or the surrounding areas in Japan and all were native Japanese. In recent years, this geographical region has had little immigration by different ethnic groups. The subjects included 73 mothers who had a PTB and 341 mothers who had a term birth (TB, a birth between 37 and 41 weeks of gestation). PTBs were also subdivided according to gestational age: 12.3% of PTBs occurred at <28 weeks (extreme prematurity), 15.1% at 28–31 weeks (severe prematurity), 27.4% at 32–33 weeks (moderate prematurity) and 45.2% at 34–36 weeks (near term). The overall rates of PTB and LBW were approximately 18 and 25% in this population, as compared with the national average of 5.7 and 9.4%, respectively (Mothers’ and Children's Health and Welfare Association, 2007). Such high rates of PTB and LBW in tertiary hospitals have been observed elsewhere in Japan (Kawamata et al., 2007). The study was conducted with informed consent of all subjects and was approved by the Institutional Ethical Board for Human Gene and Genome Studies of Hokkaido University Graduate School of Medicine.
The characteristics of the women, divided according to their gestational age at birth are shown in Table I. The maternal mean (SD) age at the time of delivery and gestational age were 31.4 (5.2) years and 37.9 (2.9) weeks, respectively. There were 50 women (12.9%) who continued smoking cigarettes and 80 women (21.1%) who continued alcohol consumption at least once a month throughout pregnancy. The mean (SD) birthweight of the newborns was 2.78 (0.63) kg. We found no significant differences in maternal age at birth, parity, cigarette smoking status, alcohol use during pregnancy or infant gender between the mothers who had a PTB and the mothers who had a TB. The etiologies of the 73 cases of PTB were classified as spontaneous (n = 43) or medically indicated (n = 30), according to the published guidelines (Pennell et al., 2007). Spontaneous PTB were comprised of preterm labor leading to PTB (idiopathic PTB, 51.2%) and preterm premature rupture of the membranes (PPROM, 48.8%).
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Selection and determination of proinflammatory cytokine polymorphisms
We selected six common polymorphisms of proinflammatory cytokines, with minor allele frequencies of at least 10% in a Japanese population according to a SNP database, such as the International Hapmap Project (Hapmap Homepage, 2006). Each polymorphism predicted a functional change because it was located in the coding region with an amino acid substitution or in the 5'-flanking region, especially in the transcription factor binding site (Table II).
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Genomic DNA was extracted from lymphocytes of peripheral blood using the QIAamp or EZ1 DNA blood kit (QIAGEN, Hilden, Germany), according to the manufacturer's instructions. We genotyped each polymorphism by allelic discrimination using fluorogenic probes and the 5' nuclease (TaqMan) assay, as previously described (Sata et al., 2006). TaqMan® SNP Genotyping Assays for each polymorphism were obtained from Applied Biosystems (Foster City, CA, USA). All probe-primer sets were designed to function using universal reaction and cycling conditions. Genotyping was performed in 10 µl reactions containing approximately 40 ng genomic DNA, 0.5 µl 20x TaqMan® SNP Genotyping Assay Mix (consisting of unlabeled PCR primers, and FAM and VIC dye-labeled TaqMan® MGB probes) and 5.0 µl of 2x Taqman® Universal PCR Master Mixture. Real-time PCR was performed on a 7500 Real-time PCR System (Applied Biosystems) using a protocol consisting of incubation at 50°C for 2 min and 95°C for 10 min, followed by 40 cycles of denaturation at 92°C for 15 s and annealing/extension at 60°C for 1 min. FAM and VIC fluorescence levels of PCR products were measured at 60°C for 1 min, resulting in the clear identification of all three genotypes in these polymorphisms on a two-dimensional graph. We confirmed no contamination by using a no template control. The samples that had not been clearly classified into genotypes the first time and a small number of other samples were analyzed using positive controls as well as a no template control. Finally, at least two researchers or technicians confirmed that all the samples were clearly classified into genotypes.
Statistical analyses
The differences in frequency of each characteristic between the PTB and TB groups were examined by a chi-square test. An unconditional logistic regression model was used to evaluate the associations between maternal proinflammatory cytokine genotypes and PTB, LBW or IUGR (<10th percentile of birthweights or less than the mean 1.5 SD of the birthweight). We calculated non-adjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype together with dominant and recessive genotype models by unconditional logistic regression analysis. As confounding factors, maternal age at birth (continuous), parity (never = 0 and any = 1), cigarette smoking status (none = 0 and continuous = 1), alcohol use (none = 0 and continuous = 1) during pregnancy and infant gender (female=0 and male=1) were considered (Table I). Bonferroni correction was performed as a multiple comparison test. Hardy–Weinberg equilibrium analyses were performed to compare observed and expected genotype frequencies using a chi-square test. The haplotype was analyzed using Haploview, version 4.0, based on the expectation-maximization algorithm (Barrett et al., 2005), and linkage disequilibrium between loci was measured using Lewontin's D’ (Hedrick, 1987). Statistical analyses were performed using SPSS software for Windows, version 15.0 (SPSS, Chicago, IL, USA).
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Results |
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The frequencies of the common inflammatory cytokine genotypes were compared between 73 mothers who had a PTB and 341 control mothers who had a TB in a Japanese population (Table III). The distribution of genotypes in each group was in Hardy–Weinberg equilibrium (chi-square test, P > 0.05). We found significantly increased risks for PTB in the IL1A –889C/T and +4845G/T groups. In this analysis, we considered maternal age at birth, parity, cigarette smoking status, alcohol use during pregnancy and infant gender as confounding factors (Table III). However, the adjusted results were nearly the same as the crude results. The risk of a PTB significantly increased in women carrying the IL1A –889T allele (CC genotype [reference]; CT genotype, OR: 2.5; 95% CI: 1.4–4.8, P < 0.01; CT+TT genotypes [dominant genotype model], OR: 2.5, 95% CI: 1.3–4.6, P < 0.01). Similarly, the risk of a PTB significantly increased in women carrying the IL1A +4845T allele (GG genotype [reference]; GT genotype, OR: 2.4, 95% CI: 1.3–4.4, P < 0.01; GT+TT genotypes [dominant genotype model], OR: 2.3, 95% CI: 1.2–4.2, P < 0.01). However, we found no significant difference between the distributions of other genotypes in the two groups (P > 0.05).
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We evaluated the risk of PTB in the subgroups of patients with spontaneous PTB classified into idiopathic PTB and PPROM; (Table III). We found significant increased risks for both idiopathic PTB and medically indicated PTB for those with IL1A –889C/T and +4845G/T polymorphisms, whereas no significant increased risks existed for PPROM for those with these polymorphisms.
There were two haplotype blocks identified in the present study: (i) IL1A –889C/T and +4845G/T, located on chromosome 2q14 (Block 1), and (ii) IL1B –511C/T and –31C/T, located on chromosome 2q14 (Block 2, Table IV). The highest degree of linkage disequilibrium was observed between polymorphisms IL1A –889C/T and +4845G/T (D' = 0.98) and between polymorphisms IL1B –511C/T and –31C/T (D' = 0.98). The frequency of the IL1A TT haplotype in mothers who had a PTB was significantly higher than those who had a TB (P = 0.0003), whereas the frequency of the IL1A CG haplotype in mothers who had a PTB was significantly lower compared with those who had a TB (P = 0.0006). The permutation test was conducted 10 000 times and the statistical significance persisted (P = 0.01 for both). The risk of a PTB significantly increased in women carrying the IL1A TT haplotype (non-carriers of TT haplotype [reference]; carriers of TT haplotype, OR: 2.5; 95% CI: 1.5–4.2, P < 0.001), whereas the risk of a PTB significantly decreased in women carrying the IL1A CG haplotype (non-carriers of CG haplotype [reference]; carriers of CG haplotype, OR: 0.4; 95% CI: 0.3–0.7, P < 0.001). On the other hand, there were no significant changes in any haplotype frequencies of the IL1B block.
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The frequencies of the inflammatory cytokine genotypes were also compared between 104 mothers who had a LBW infant and 310 control mothers in a Japanese population (Table V). We found significantly increased risks for LBW infants in IL1A –889C/T and +4845G/T polymorphisms. However, there were no significant differences in the distribution of other genotypes within the two groups (P > 0.05). We also evaluated the risk of IUGR using two different definitions of IUGR, which are used in Japan, as shown in Table V. We did not find any significantly increased nor decreased risks for IUGR with any polymorphism.
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Discussion |
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We assessed the possible role of common proinflammatory cytokine genes observed in a Japanese population in the present study. To the best of our knowledge, this is the first report demonstrating significant associations between maternal IL1A polymorphisms and PTB. The risk of PTB was significantly increased in women carrying the IL1A –889T or the IL1A +4845T alleles. We confirmed these significant risks in cases with idiopathic PTB, where the causes are closely associated with premature labor due to the production of inflammatory cytokines (Keelan et al., 2003). We found that the IL1A locus was associated with idiopathic PTB, but not with PPROM. It is suggested that a specific mechanism, such as an abnormality of IL1-
production, might lead to idiopathic PTB, which is quite different from the etiology of PPROM. Such etiological differences between idiopathic PTB and PPROM have been reported: the risk factors for idiopathic PTB include personal obstetrical history, social factors and lifestyle, whereas those for PPROM include disadvantaged population, African American ethnicity and infection (Moutquin, 2003). Thus, births that follow spontaneous preterm labour and PPROM are regarded as a syndrome resulting from multiple causes, including infection or inflammation, vascular disease and uterine overdistension (Goldenberg et al., 2008). In the present study, however, there was no significant difference in the distribution of gestational age between idiopathic PTB and PPROM.
The IL1A –889C/T polymorphism is associated with susceptibility to several diseases, such as juvenile rheumatoid arthritis (McDowell et al., 1995), osteoarthritis (Loughlin et al., 2002), periodontal disease (Kornman et al., 1997) and Alzheimer's disease (Rogers, 2000). These studies have suggested that the IL1A –889T allele alters the transcriptional ability of IL1A, resulting in an aberrant production of IL-1 in these diseases. The IL1A –889TT genotype creates a consensus site for the transcription factor, Skn-1, and is associated with a significant increase in promoter activity compared with the –889CC genotype (Hulkkonen et al., 2000). A slight increase in IL-1 mRNA and protein levels in the plasma has been detected in a carrier of the IL1A –889TT genotype (Dominici et al., 2002). Regarding the other polymorphism, one of the risk factors of PTB and periodontal disease is also related to the polymorphisms of IL1A +4845G/T (Offenbacher et al., 2001; Thomson et al., 2001; Li et al., 2004). IL1A +4845T (114S) is associated with risks of inflammatory disorders, reflecting increased IL-1 production in carriers of this allele and the IL1A –889T allele (Thomson et al., 2001).
In the present study, the frequency of the IL1A TT haplotype in mothers who had a PTB was remarkably higher than in those who had a TB (P < 0.001), whereas the CG haplotype in mothers who had a PTB was remarkably lower than in those who had a TB (P < 0.001; Table IV). Although the statistical significance for the risk of PTB in the IL1A –889C/T and +4845G/T polymorphisms was not preserved by multiple comparison tests using the Bonferroni correction, the statistical significance for the risk of PTB in the IL1A TT and CG haplotypes persisted through 10 000 permutation tests (P = 0.01 for both). These findings suggest that the IL1A TT haplotype may be a potential modifier for the risk of PTB, whereas the CG haplotype may be rather protective against PTB. On the other hand, the association between the IL1A polymorphisms and LBW seemed to be a secondary outcome dependent on PTB because its statistical significance was completely lost by the logistic analysis adjusted for gestational age (data not shown).
The present study has several limitations. First, our sample size was not large enough, especially among the subgroups of PTB, to examine possible associations with common proinflammatory cytokine polymorphisms in a Japanese population. However, it was sufficient to detect a significant risk for PTB with the IL1A polymorphisms. Second, the functional consequences of IL1A polymorphisms could not be examined in the present study; previous investigations, however, have suggested functional changes in subjects carrying those polymorphisms (Hulkkonen et al., 2000; Dominici et al., 2002; Li et al., 2004). Third, we could only obtain partial information for the subjects regarding socio-economic status, maternal weight and height before and during pregnancy, previous histories of PTB, LBW, cervical procedures and interventions in our registration system. Therefore, we could not exclude these data as possible confounding factors in the statistical analyses. However, the selected confounding factors shown in Table I, which were often used in previous studies, did not affect our findings whatsoever. Fourth, our study population was comprised entirely of Japanese women. A previous report found that the IL1A +4845G/T polymorphism was modestly associated with spontaneous PTB in Caucasian women, whereas it had no association with spontaneous PTB in African American women (Engel et al., 2005). Thus, the IL1A polymorphisms vary with ethnicity. Fifth, it was impossible to assess whether the variant in the IL1A gene might be the key or whether it is something they both tag in the present study because the two SNPs in IL1A were in high LD. Further studies with a larger population are needed to elucidate whether polymorphisms and haplotypes in IL1A and the IL1 gene cluster are associated with which types of PTB in each ethnic group.
In conclusion, our findings suggest that polymorphisms and haplotypes in the IL1A gene are associated with PTB in Japanese women.
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This work was supported, in part, by Grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science, the Japan Ministry of Health, Labour and Welfare, and the Japan Ministry of Education, Culture, Sports, Science and Technology.
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Acknowledgements |
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We thank Dr M. Narugami, Ms. Y. Matsumoto, Ms. A. Makino and Ms. Y. Yamaoka for their technical assistance.
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Submitted on July 21, 2008; resubmitted on December 10, 2008; accepted on December 17, 2008.
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