Abstract
Introduction:
Preterm birth is the major cause of mortality and morbidity in neonates. Intrauterine infection and/or inflammatory response are evident in 60–70% of spontaneous preterm births (SPTBs). Genetic factors significantly increase this risk. However, the genetic background associated with SPTB is poorly understood. Surfactant protein (SP) A, SP-D, and mannose-binding lectin (MBL) are structurally and functionally related collectins that bind pathogen-associated molecular patterns, and mostly suppress innate immune responses.
Results:
We detected an overrepresentation of the methionine allele of the SFTPD gene (encoding SP-D) Met31Thr polymorphism in preterm infants as compared to term infants. This association was highly significant in infants of families with recurrent SPTBs (P = 0.001, odds ratio = 1.65, 95% confidence interval = 1.22–2.22); however, there was no such association with SFTPD in the mothers of these infants. Polymorphism of the genes encoding SP-A and MBL did not influence the risk of SPTB.
Discussion:
Our results suggest that the fetal SFTPD Met31Thr polymorphism plays a significant role in genetic predisposition to SPTB. We propose that fetal immune responses influence sensitivity to preterm labor–inducing signals.
Methods:
Genes encoding SP-A, SP-D, and MBL were investigated as potential candidates for association with SPTB in a population of preterm singleton infants (n = 406) and their mothers (n = 308), and in mothers with term deliveries (n = 201) and their infants (n = 201), all originating from northern Finland.
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Main
Preterm birth (a birth that occurs before 37 completed weeks of gestation) is a serious global health problem; ~10% of all infants are born preterm (1). Prematurity is the main cause of mortality and morbidity in newborn infants. Preterm infants are at an increased risk of developing serious chronic diseases, including bronchopulmonary dysplasia, retinopathy of prematurity, cerebral palsy, and cognitive problems (2). More than 60% of all preterm births are due to spontaneous onset of labor. In multiple pregnancies, the risk of spontaneous preterm birth (SPTB) is several-fold higher. Bacterial vaginosis, ascending infections of the genital tract, and systemic infections, including asymptomatic infections of the urinary tract, serve as major risk factors. In 25% of all preterm births, preterm premature rupture of the fetal membranes precedes the spontaneous onset of labor (3). Taken together, most risk factors for SPTB are related to intrauterine infection or inflammatory reaction.
There is evidence to suggest that genetics plays an important role in the risk of preterm birth. There is a higher incidence of preterm deliveries among mothers with a history of previous such deliveries (4); it is therefore likely that specific maternal and/or fetal genotypes are involved (5). Several genes have been considered as candidates for an association with SPTB (6), and the first genome-wide linkage analysis of SPTB was recently published (7). Given that infection and inflammation are involved in the initiation of SPTB, genes encoding proteins involved in the regulation of inflammatory mediators are plausible candidate genes. Indeed, polymorphism in several genes associated with inflammation pathways, including the cytokine genes encoding tumor necrosis factor-α and interleukin-4, have been reported to associate with preterm birth in mothers with preterm labor and in fetuses born preterm (6). Despite the reported associations, the genetic background of this multifactorial phenotype is still poorly understood. To date, genome-wide association analyses have not been reported.
Collectins are a family of C-type lectins with collagenous domains. Members of this family, including surfactant protein (SP) A, SP-D, and mannose-binding lectin (MBL), participate in several immunoregulatory functions and bind the carbohydrate domains of invading microorganisms (8). SP-A and -D are produced mainly in the type II lung alveolar cells but are also expressed in other cell types. These collectins are present in several tissues and compartments, including the airways, female genital tract, amniotic fluid, extraembryonic tissues, and blood (9). They have partially overlapping roles in host defense, particularly in the lung. Both SP-A and SP-D participate in the killing and clearance of pathogens and as opsonins;, they also modulate inflammatory responses by interacting directly with pattern recognition receptors (10). In addition, SP-A and SP-D have complex roles in pulmonary surfactant metabolism and homeostasis (11). MBL is produced mainly in the liver and secreted into the blood. It functions by opsonization and activation of the lectin pathway of the complement system, thereby leading to lysis of MBL-bound pathogens (12).
We propose that polymorphisms in collectin genes have a role in susceptibility to SPTB. The aim of this study was to assess the genes encoding SP-A (SFTPA1 and SFTPA2), SP-D (SFTPD), and MBL (MBL2) for their possible role in SPTB in a genetically homogeneous northern Finnish population. Both fetal and maternal polymorphisms were considered. We also hypothesized that families with recurrent SPTBs may have a stronger genetic predisposition to this outcome as compared to families in which SPTBs were only sporadic. We found that, a common polymorphism of the gene encoding SP-D was associated with SPTB in preterm infants of families with recurrent SPTBs. Interestingly, this variation, Met31Thr, has previously been shown to influence the concentration, oligomerization, and binding properties of SP-D (13,14,15).
Results
SP-A and SP-D Gene Polymorphisms
The frequency distribution of the SFTPD amino acid 31 allele was significantly different in SPTB infants of families with recurrent SPTBs as compared to controls; the frequency of the Met allele was 0.717 in cases and 0.605 in controls (nominal P = 0.001, permutation-corrected P = 0.008) ( Table 1 ). The association of Met31Thr with SPTB in these infants was further analyzed using logistic regression analysis under three alternative models (codominant, dominant, and recessive) with sex as a covariate ( Table 2 ). Logistic regression revealed that this polymorphism significantly influenced the SPTB phenotype under the codominant model (Met/Met vs. Met/Thr vs. Thr/Thr, P = 0.002) and the recessive model (Met/Met vs. Met/Thr and Thr/Thr, P = 0.0005, odds ratio for Met/Met 2.06). No significant differences were observed among the mothers as regards the SFTPD Met31Thr allele frequencies ( Table 1 ). In families with recurrent SPTB, the allele distribution in term siblings (n = 176) was comparable (0.707 and 0.293 for the Met and Thr alleles, respectively) to that in preterm siblings.
The frequency distributions of the alleles of SFTPA1 Val50Leu and SFTPA2 Gln223Lys were similar in SPTB infants or mothers ( Table 1 ), as well as in term siblings of SPTB infants (data not shown), compared to control groups; this continued to hold true even after the SPTB cases were subdivided according to the number of SPTB cases in the family. The frequency distributions of the SP polymorphisms did not differ significantly between SPTB infants with gestational ages of <32 weeks (n = 139) and those of 32–36 weeks (n = 263) (minor allele frequencies of 0.381 and 0.409 for SFTPA1 Val50Leu, 0.194 and 0.182 for SFTPA2 Gln223Lys, and 0.371 and 0.317 for SFTPD Met31Thr, respectively). Additional stratification by gender, maternal smoking, and presence/absence of preterm premature rupture of the fetal membranes did not reveal significant differences for the SP polymorphism frequencies across the subgroups (data not shown). The SP gene polymorphisms did not deviate from Hardy–Weinberg equilibrium. The SFTPA1 and SFTPA2 SNPs displayed moderate linkage disequilibrium (LD) (D′ = 0.8, r2 = 0.24; Figure 1 ) and were therefore also analyzed as haplotypes. However, this analysis did not reveal any significant differences between SPTB infants or mothers, and controls (data not shown). Although the SFTPD locus lies in close physical proximity to the SFTPA1 and SFTPA2 loci on chromosome 10, the SFTPD Met31Thr polymorphism was not in LD with the two SP-A gene polymorphisms ( Figure 1 ). Therefore, we did not analyze intergenic haplotypes of these three genes.
MBL2 Polymorphisms and Haplotypes
As expected, the MBL2 promoter polymorphisms –550 (H/L) and –221 (X/Y), and exon 1 Gly54Asp (A/B) displayed high LD ( Figure 1 ). Altogether, eight 3-SNP MBL2 haplotypes were predicted. Of these, four (HYA, LXA, LYA, and LYB) were common (frequencies >0.05), whereas the other four (LXB, HYB, HXA, and HXB) were rare (frequencies <0.01). No significant differences were detected between the SPTB and control groups with respect to MBL2 allele or haplotype frequencies ( Table 3 ). Allele frequencies of term siblings of SPTB infants were comparable to those of their preterm siblings (data not shown).
Allele frequency distributions did not differ significantly between SPTB infants with gestational ages of <32 weeks (n = 131) and those of 32–36 weeks (n = 261) for any of the MBL2 polymorphisms (minor allele frequencies of 0.357 and 0.420 for promoter –550; 0.229 and 0.252 for promoter –221; and 0.115 and 0.132 for Gly54Asp, respectively) or haplotypes (data not shown). When the study population was stratified by gender, maternal smoking, or presence/absence of preterm premature rupture of the fetal membranes, there were no significant differences in allele or haplotype frequencies among the subgroups (data not shown). The MBL2 polymorphisms that were analyzed did not deviate from Hardy–Weinberg equilibrium.
MBL2 haplogenotypes are known to be associated with differences in serum MBL concentrations (16,17). Therefore, the haplogenotypes were ranked into classes according to their MBL scores (1–10), reflecting their varying potential to induce high-serum MBL concentrations as described previously (17), and MBL scores were calculated for each of the study groups. The frequencies of the high (MBL scores 6–10), intermediate (MBL scores 3–5), and low (MBL scores 1–2) MBL-conferring genotype groups were 70.8, 21.4, and 7.8%, respectively, in SPTB infants; 75.3, 19.7, and 5.1, respectively, in control infants; and 77.8, 16.8, and 5.4, respectively, in term siblings of SPTB infants. In mothers with SPTB and control mothers, the frequencies were 71.8 and 76% for high, 20.1 and 18.5% for intermediate, and 8.1 and 5.5% for low MBL-conferring genotype groups, respectively. No significant differences were detected in haplogenotype frequencies (data not shown) or MBL scores ( Figure 2 ) between SPTB infants or mothers and controls; the median MBL score was 7 in all of the groups. However, the median MBL score was higher (median of 8) in term siblings of SPTB infants (P = 0.03 in comparison with term infants in the control group and P = 0.005 in comparison with SPTB infants) ( Figure 2 ). When the SPTB infants or their mothers were divided into groups according to the nature of SPTBs in the family (recurrent or sporadic), or according to gestational age, no significant differences were observed across the subgroups (data not shown).
Discussion
In SPTBs, the prominent feature is a mostly silent infection or inflammation involving the urogenital tract and the fetoplacental compartments (3). Although acquired factors play an important role, it is evident that susceptibility to SPTB is often an inherited feature, conferred by genetic factors of in the mother and the fetus (6). Given the important role of intrauterine infection and inflammation, we chose to explore variations of the genes encoding SP-A, SP-D, and MBL, which have important roles in innate immunity. We found an association between a nonsynonymous variation at codon 31 of the SFTPD gene and the risk of SPTB when the outcome phenotype was being born preterm (affected fetus phenotype) ( Table 1 ). To our knowledge, this is the first study to report an association of this gene with SPTB.
According to our results, the SFTPD Met31Thr polymorphism can be considered a potential factor to explain genetic susceptibility to SPTB. We observed a significant difference in the allele frequency of SFTPD methionine 31 (P = 0.001) between term infants of families with exclusively term deliveries and preterm infants of families with multiple preterm deliveries ( Table 1 ). This association was further verified by logistic regression analysis, which suggested that the Met31Thr genotypes influence the SPTB phenotype under the codominant (P = 0.002) and recessive models (P = 0.0005; Table 2 ). Because the allele distribution of Met31Thr was similar in SPTB infants and their term siblings, this polymorphism may have a permissive role, possibly by influencing resistance to preterm labor–promoting signals. With the phenotype of giving birth preterm (affected mother phenotype), no significant associations were observed ( Table 1 ). In an epidemiological study of large families with predisposition to preterm birth, the genome of the mother was shown to influence the duration of gestation of her preterm infant, whereas the fetal genome influenced the premature birth per se but had no detectable influence on the degree of prematurity (18). This is consistent with the proposed permissive role for the fetal SFTPD Met31Thr polymorphism.
The biological significance of the associated SFTPD polymorphism has been studied previously. This polymorphism influences serum SP-D concentrations and oligomerization of the SP-D protein (13,14,15). The significance of the Met31Thr polymorphism is probably due to its influence on the binding of pathogen-associated molecular patterns. Indeed, highly multimerized and lower-molecular-weight forms of SP-D have been shown to exhibit differential binding to microbial ligands, with the former preferentially binding mannan and lipoteichoic acid and the latter, lipopolysaccharide and peptidoglycan (13,19). In the Finnish population, term-born young children carrying the SFTPD codon 31 methionine allele were shown to be predisposed to severe respiratory syncytial virus infection (20). In other studies, the alternative allele, threonine, was overrepresented in patients with tuberculosis in a Mexican population (21) and in those with allergic rhinitis in a Chinese population (22). This further suggests that genetic susceptibility depends on the specific ligand that causes the inflammatory challenge.
The potential role of SFTPD polymorphism in the process of preterm labor remains to be investigated. Although the main production site for SP-D is the lung, it is present in other tissues including the female reproductive tract, placenta, and fetal membranes (9). The concentration of this protein increases in the amniotic fluid as gestation proceeds (23). SP-D is currently thought to play a dual role in inflammation, with either proinflammatory or anti-inflammatory effects defined by the binding orientation of the protein (24), possibly depending on the degree of SP-D multimerization. Our study finding of an association between an SFTPD polymorphism and SPTB may be related to this dual function, which may be partly defined by the alternative variants of the Met31Thr polymorphism.
In this study, the genes encoding SP-A and MBL were not found to be associated with SPTB. According to the findings of an experimental study, SP-A in the amniotic fluid potentially regulates the duration of pregnancy, as implicated by the fact that its concentration levels increase strikingly as gestation proceeds toward term labor; moreover, a high concentration of SP-A was shown to induce proinflammatory cytokine expression in macrophages in vitro (25). However, in our study, the polymorphisms of SFTPA1 and SFTPA2 did not show any association with SPTB. In the case of the MBL2 gene, our study finding of an absence of association was unexpected, because the association of distinct MBL2 polymorphisms and haplotypes with preterm birth has been previously demonstrated (26,27,28,29). However, the earlier studies were performed in different populations and there are inconsistencies in phenotype definitions of preterm birth. In our study, the median MBL score, which indicates the potential to induce high serum MBL concentrations, tended to be higher in the term siblings (median of 8) of the SPTB infants as compared to all other groups (median of 7) ( Figure 2 ). This may actually mean that these individuals were “protected” from SPTB because of the presence of the higher serum MBL-conferring genotypes as compared to their preterm-born siblings. The roles of MBL and the pulmonary collectins in the etiology of SPTB require further investigation.
The strengths of the study include the use of a carefully selected, relatively homogeneous population (30), consideration of pregnancy history, and analysis of both maternal and fetal alleles. To avoid type I errors, we used a limited number of polymorphisms and applied corrections for multiple testing for the allele and haplotype frequency comparisons. However, this study had some limitations. According to the dbSNP database, 31, 30, 35, and 32 common SNPs exist within SFTPA1, SFTPA2, SFTPD, and MBL2, respectively, in Caucasians. Because our sample sizes did not provide adequate power to detect associations with a large number of polymorphisms, we decided to analyze only the SNPs that were most likely to have biological significance rather than aim at capturing complete variation of these genes. As a consequence, the analyzed polymorphisms captured only a portion of the variation within these genes, and our results do not exclude the possibility that other polymorphisms within these genes could affect the SPTB phenotype. For the SFTPD polymorphism, the observed association may be attributable to LD with other potential functional variations within the gene or with other genes in close proximity. Two other common nonsynonymous variations located on the collagen domain–encoding region are known to exist within the SFTPD gene. Three of the four common MBL2 SNPs that correlate with MBL concentrations (16) were studied, with a careful analysis of haplogenotypes and associated MBL scores. However, P/Q variation, which is considered to be one of the potentially significant variations, was not analyzed. Therefore, we were not able to discriminate between the common MBL2 LYPA and LYQA haplotypes.
In summary, a specific SFTPD polymorphism that may increase the concentration and aggregate size of SP-D showed association with SPTB when the phenotype was defined as being spontaneously born preterm. SP-D and other collectins may prove to be important proteins involved in activation of the labor process when the fetoplacental compartment is challenged with infection.
Methods
Study Population and DNA Sample Preparation
The case study population consisted of mothers and their preterm infants (gestational age <37 weeks); all the women had delivered after spontaneous onset of labor. The participants were selected retrospectively from the 1973–2003 birth diaries of Oulu University Hospital, and prospectively during 2003–2005. The exclusion criteria were factors that are known to contribute to the risk of preterm birth (multiple gestation, preeclampsia, polyhydramnios, septic infection, and fetus with congenital disease), and chronic disease or alcohol/narcotics abuse in the mother. The control population consisted exclusively of mothers who had experienced at least three term births (gestational age >37 weeks; n = 201) and their singleton infants (n = 201), sampled prospectively from Oulu University Hospital between 2004 and 2007. All of the families that were studied originated from northern Finland, where the population is known to exhibit genetic homogeneity (30). The two outcome phenotypes studied were (i) being delivered spontaneously preterm (affected fetus/infant phenotype), and (ii) delivering the infant spontaneously preterm (affected mother phenotype). Written informed consent was obtained for use of the samples, and the study was approved by the ethics committee of Oulu University Hospital.
The clinical characteristics of the case study population are presented in Table 4 . The population comprised two groups: (i) mothers who had given birth preterm (gestational age <37 weeks) at least twice (n = 94), and their preterm infants (n = 189) (“recurrent SPTB”), and (ii) mothers who had given birth preterm once (n = 214), and their preterm infants (n = 217) (“sporadic SPTB”). The mean numbers of children in the families with recurrent and sporadic SPTBs were 4.7 and 2.9, respectively, consistent with a high fertility rate in this region. In 35% of all cases, preterm premature rupture of the fetal membranes preceded the SPTB ( Table 4 ). We also analyzed data from term-born siblings (n = 176) of preterm infants belonging to families with recurrent SPTBs.
Genomic DNA was extracted from whole-blood specimens (n = 706) using the Puregene DNA Isolation Kit (Gentra Systems, Minneapolis, MN) and UltraClean DNA Blood Isolation Kit (MO BIO Laboratories, Carlsbad, CA). Chelex 100 (Bio-Rad, Hercules, CA) was used to extract genomic DNA from buccal cells (n = 586). Buccal samples were whole-genome amplified using an Illustra GenomePhi V2 DNA Amplification Kit (GE Healthcare, Buckinghamshire, UK). Ethidium bromide–stained agarose gels and UV absorbance measurements were used to control for the quality and quantity of the whole-genome amplified samples.
SNP Selection and Genotyping
For each of the three SP genes, one nonsynonymous single-nucleotide polymorphism (SNP) was analyzed: SFTPA1 SNP Val50Leu, SFTPA2 SNP Gln223Lys, and SFTPD SNP Met31Thr, with accession numbers rs1136450, rs1965708, and rs721917, respectively, in the dbSNP database (http://ncbi.nih.gov/SNP). The SFTPA1 and SFTPA2 SNPs were selected because of their known utility as tagging SNPs, and also because they are located at the functional domains of the SP-A1 and SP-A2 polypeptides (collagenous and carbohydrate recognition regions, respectively) (31,32). The SFTPD Met31Thr was selected for study because this variation has previously been shown to affect SP-D oligomerization and concentration in the serum (13,14,15). Of the six MBL2 SNPs known to correlate with serum MBL concentrations (16), three were included in this study: the promoter variations –550 (H/L) and –221 (X/Y) and the exon 1 variation Gly54Asp (A/B), with accession numbers rs11003125, rs7096206, and rs1800450, respectively, in the dbSNP database. Given their low minor allele frequency (<0.05) in Caucasians, the MBL2 exon 1 variations Cys52Arg (A/D, rs5030737) and Gly57Glu (A/C, rs1800451) were not included in the analysis. The P/Q variation (rs7095891) at position +4 in the 5′ untranslated region was excluded from analysis because of deviation from Hardy–Weinberg equilibrium.
The SFTPA1, SFTPA2, and SFTPD SNPs were genotyped using PCR-restriction fragment-length polymorphism analysis. Two rounds of PCR were first performed to amplify the region surrounding each SNP. One of the primers in the reamplification had either a one-nucleotide or a two-nucleotide mismatch, resulting in the creation of an arbitrary recognition site for the restriction endonucleases DdeI, TaqI, and FspI for the SFTPA1, SFTPA2, and SFTPD SNPs, respectively, for the purpose of genotype detection. Restriction endonucleases were purchased from New England Biolabs (Beverly, MA). The MBL2 SNPs were genotyped by template-directed dye-terminator incorporation with fluorescence polarization detection (33) using AcycloPrime II SNP Detection Kits (Perkin Elmer Life Sciences, Boston, MA). Details of the PCR and SNP primers used are available on request.
Statistical Analysis, Haplotype Prediction, and Study Power
Haploview, v. 4.2 (34) was used for Hardy–Weinberg equilibrium testing and to obtain pairwise LD (D′ and r2) values, as well as for estimation of haplotype frequencies and comparisons of allele and haplotype frequencies. Haploview creates haplotype frequency estimates based on an accelerated expectation maximization algorithm, and uses the χ2 test for case–control analysis of alleles and haplotypes. The P values obtained from allele and haplotype analyses were corrected for multiple testing using 10,000 permutations; a corrected P value <0.05 was considered significant. Genotype frequency comparisons (logistic regression analysis with fetal sex as a covariate under codominant, dominant, and recessive models) and calculations of common odds ratios were performed using Predictive Analytics SoftWare statistics, v. 17.0.3 (IBM SPSS). MBL2 phased haplotypes were constructed using SNPHAP, v. 1.3.1. (http://www-gene.cimr.cam.ac.uk/clayton/software). MBL2 haplogenotypes were classified according to their potential to induce high serum MBL concentrations into classes ranging from 1 (lowest potential) to 10 (highest potential), as described previously (17), and subsequently analyzed by means of the nonparametric Mann–Whitney U-test using Predictive Analytics SoftWare statistics. The genetic power of the study was estimated using Genetic Power Calculator (http://pngu.mgh.harvard.edu/~purcell/gpc) (35). Using the allelic 1 degree of freedom test and an additive risk model, and assuming a causal SNP with a minor allele frequency ranging from 0.1 to 0.4 and a prevalence of 0.05 for SPTB, our sample size was estimated to provide 80% power (α = 0.008, taking into account multiple testing of six SNPs) to detect genotypic relative risks of 1.6–2.0 for heterozygotes and 2.3–2.9 for homozygotes in the infants. Using the same parameters, the sample size in the mothers was estimated to provide 80% power to detect relative risks of 1.7–2.0 for the heterozygous and 2.4–3.0 for the homozygous risk genotypes.
Statement of Financial Support
This work was supported by grants from the Finnish Academy and the Sigrid Jusélius Foundation (M.H.), and the Foundation of Pediatric Research in Finland (R.H.).
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The authors thank Maarit Haarala, Outi Kajula, Mirkka Ovaska, and Riitta Vikeväinen for sample collection and technical assistance.
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Karjalainen, M., Huusko, J., Tuohimaa, A. et al. A study of collectin genes in spontaneous preterm birth reveals an association with a common surfactant protein D gene polymorphism. Pediatr Res 71, 93–99 (2012). https://doi.org/10.1038/pr.2011.2
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DOI: https://doi.org/10.1038/pr.2011.2
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