Single-nucleotide polymorphism associations with preterm delivery: a case–control replication study and meta-analysis (original) (raw)
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Journal of Obstetrics and Gynaecology Canada, 2016
Objective: To estimate the association of a maternal factor V Leiden (FVL) mutation with SGA and preterm birth. Data sources: We performed a search of PubMed, Embase, Scopus, CINAHL, and the Cochrane Library from inception to April 2016 for cohort and case-control studies of women with FVL mutation and associated outcomes of SGA and preterm birth that included a reference group without FVL mutation. Additional studies were identified from reference lists of relevant research and review articles. Study selection: Two authors (JKB, AMO) independently examined the abstracts of the potentially eligible studies, and full texts of eligible studies were retrieved for further evaluation. Disagreements were resolved by consensus. We identified 42 studies suitable for inclusion in the meta-analysis. Data extraction: Thirty-two studies evaluated SGA, and 18 studies assessed preterm birth. Study quality was assessed using the Newcastle Ottawa Scale. A random effects model with inverse variance weighting was used to calculate pooled ORs and 95% CIs. Subgroup analyses were performed by study design. Data synthesis: The overall OR associating FVL mutation with SGA was significant (OR 1.40, 95% CI 1.18 to 1.67). Analysis of 13 cohort studies resulted in an OR of 1.20 (95% CI 1.03 to 1.41), and data from 19 case-control studies yielded an OR of 1.86 (95% CI 1.35 to 2.56). There was no significant association between FVL mutation and preterm birth (OR 1.17, 95% CI 1.00 to 1.37) when all groups were studied, but the association was significant for casecontrol studies alone (OR 1.40, 95% CI 1.05 to 1.86). Conclusion: There is an increased risk for SGA in pregnancies complicated by FVL mutation in both cohort and case-control study designs. The risk of preterm birth with FVL mutation is less clear, although there is conflicting evidence from cohort and case-control studies regarding the risk of preterm birth associated with FVL mutation. Résumé Objectif : Évaluer le lien entre la mutation du facteur V Leiden (FVL) chez la mère et le faible poids pour l'âge gestationnel et la prématurité. Sources de données : Nous avons cherché dans PubMed, Embase, Scopus, CINAHL et la Bibliothèque Cochrane, parmi tous les articles publiés avant avril 2016, des études de cohorte et des études cas-témoins portant sur des femmes ayant une mutation du FVL et les problèmes associés que sont le faible poids pour l'âge gestationnel et la prématurité. Les études devaient aussi inclure un groupe témoin sans mutation du FVL. D'autres études ont été trouvées dans les références des revues et des articles de recherche pertinents. Sélection des études : Deux auteurs ont examiné séparément les résumés des études qui pouvaient être incluses dans l'analyse, puis les textes complets des études retenues à cette étape ont été obtenus aux fins d'évaluation approfondie. Les désaccords se sont réglés par décision consensuelle. Nous avons ainsi recensé 42 études pertinentes pour notre méta-analyse. Extraction des données : Parmi les études retenues, 32 portaient sur le faible poids pour l'âge gestationnel, et 17 sur la prématurité. La qualité des études a été évaluée au moyen de la Newcastle-Ottawa Scale. Les rapports de cotes (RC) et les intervalles de confiance (IC) à 95 % combinés ont été calculés à l'aide d'un modèle à effets aléatoires utilisant la pondération par l'inverse de la variance. Pour les analyses de sous-groupes, les études ont été séparées selon leur modèle. Synthèse des données : Le RC global associant la mutation du FVL au faible poids pour l'âge gestationnel était significatif (RC : 1,40; IC à 95 % : 1,18e1,67). Le RC des 13 études de cohorte était de 1,20 (IC à 95 % : 1,03e1,41), et celui des 19 études cas-témoins était de 1,86 (IC à 95 % : 1,35e2,56). Nous n'avons constaté aucune corrélation significative entre la mutation du FVL et la prématurité (RC : 1,17; IC à 95 % : 1,00e1,37) pour l'ensemble des groupes; toutefois, cette association était significative pour le sousgroupe des études cas-témoins (RC : 1,40; IC à 95 % : 1,05e1,86). Conclusion : Les études de cohorte et les études cas-témoins indiquent un risque accru de faible poids pour l'âge gestationnel en
Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update
BMC Genomics, 2016
Background: Preterm birth (PTB), birth at <37 weeks of gestation, is a significant global public health problem. Worldwide , about 15 million babies are born preterm each year resulting in more than a million deaths of children. Preterm neonates are more prone to problems and need intensive care hospitalization. Health issues may persist through early adulthood and even be carried on to the next generation. Majority (70 %) of PTBs are spontaneous with about a half without any apparent cause and the other half associated with a number of risk factors. Genetic factors are one of the significant risks for PTB. The focus of this review is on single nucleotide gene polymorphisms (SNPs) that are reported to be associated with PTB. Results: A comprehensive evaluation of studies on SNPs known to confer potential risk of PTB was done by performing a targeted PubMed search for the years 2007-2015 and systematically reviewing all relevant studies. Evaluation of 92 studies identified 119 candidate genes with SNPs that had potential association with PTB. The genes were associated with functions of a wide spectrum of tissue and cell types such as endocrine, tissue remodeling, vascular, metabolic, and immune and inflammatory systems. Conclusions: A number of potential functional candidate gene variants have been reported that predispose women for PTB. Understanding the complex genomic landscape of PTB needs high-throughput genome sequencing methods such as whole-exome sequencing and whole-genome sequencing approaches that will significantly enhance the understanding of PTB. Identification of high risk women, avoidance of possible risk factors, and provision of personalized health care are important to manage PTB.
Preterm Birth in Caucasians Is Associated with Coagulation and Inflammation Pathway Gene Variants
PLoS ONE, 2008
Spontaneous preterm birth (,37 weeks gestation-PTB) occurs in ,12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls) was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV) that was previously associated with PTB, factor VII (FVII), and tissue plasminogen activator (tPA). The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30610 23) and genotypic association (p = 2.0610 26) with PTB. The odds ratio (OR) for this SNP was 2.80 [CI 1.77-4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00610 23). The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA) gene for allele (p = 0.01) and genotype (p = 3.34610 24). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15-3.19] (p = 2.00610 23). Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952) and FVII (rs3211719) (p,0.001). These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB.
Scientific reports, 2018
Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried se...
Public Health Genomics, 2010
Our goal wasto produce a field synopsis of genetic associations with preterm birth and to set up a publicly available online database summarizing the data. We performed a systematic review and meta-analyses to identify genetic associations with preterm birth. We have set up a publicly available online database of genetic association data on preterm birth called PTBGene (http://ric.einstein.yu.edu/ptbgene/index.html) and report on a structured synopsis thereof as of December 1, 2008. Data on 189 polymorphisms in 84 genes have been included and 36 meta-analyses have been performed. Five gene variants (4 in maternal DNA, one in newborn DNA) have shown nominally significant associations, but all have weak epidemiological credibility. After publishing this field synopsis, the PTBGene database will be regularly updated to keep track of the evolving evidence base of genetic factors in preterm birth with the goal of promoting knowledge sharing and multicenter collaboration among preterm birth research groups.
Investigation of genetic risk factors for chronic adult diseases for association with preterm birth
Human Genetics, 2013
Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case-control study of four female cohorts with spontaneous PTB (n = 673) versus term (n = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations (P<0.05), which were more than expected (binomial test; P = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTBin the initial discovery cohort (P = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated (P = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA-DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10 −219 ). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB.
Associations between fetal inherited thrombophilia and adverse pregnancy outcomes
American Journal of Obstetrics and Gynecology, 2006
Objective: The purpose of this study was to investigate associations between fetal inherited thrombophilia and adverse pregnancy outcomes, including pregnancy-induced hypertensive disorders (PIHD), antepartum hemorrhage (APH), small-for-gestational age !10th percentile (SGA), and preterm birth (PTB). Study design: Seven hundred and seventeen cases and 609 controls were genotyped for Factor V Leiden (FVL, G1691A), Prothrombin gene mutation (PGM, G20210A), and Methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C using DNA from newborn screening cards. Results: For babies born !28 weeks' gestation, PGM was associated with an increased risk of SGA (OR 6.40, 95%CI 1.66-24.71) and APH with SGA (OR 6.35, 95%CI 1.63-24.75). Homozygous MTHFR A1298C was associated with an increased risk of SGA for babies born 28-31 weeks gestation (OR 4.00, 95%CI 1.04-15.37), and with APH and SGA for babies born !32 weeks' gestation (OR 3.57, 95%CI 1.09-11.66). Homozygous MTHFR C677T was associated with a reduced risk of PTB and SGA (OR 0.52, 95%CI 0.28-0.96) for babies born 32 to 36 weeks' gestation. Homozygous FVL decreased the risk of PTB !32 weeks' gestation (OR 0.55, 95%CI 0.31-0.98).
Genetic Polymorphisms and Spontaneous Preterm Birth
Obstetrics & Gynecology, 2007
To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. METHODS: Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. RESULTS: In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the 2 adrenergic receptor gene (ADRB2 Q27E, P,)300.؍ inducible nitric oxide synthase (iNOS or NOS2A, P,)240.؍ or thrombomodulin (G127A, P.)600.؍ Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS-922, P,)210.؍ plasminogen activator inhibitor-2 (P510.؍ and .019), and alpha adducin (ADD1, P.)740.؍ CONCLUSION: We confirm previous observations that variants of the  adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and alpha adducin may be contributors to risk of spontaneous preterm birth.