Abstract
BackgroundChorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study.MethodsPlacentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed.ResultsSixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated.ConclusionThese findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis.
Highlights
Chorioamnionitis is a common underlying cause of preterm birth (PTB)
Histologic chorioamnionitis was positively associated with clinical chorioamnionitis [Univariate Odds Ratio (OR) 6.1, 95% Confidence Intervals (CI) 2.4–17, uncorrected P ≤ 0.0001], PTB before 29 weeks and positive placental culture
Multivariable analysis confirmed that carriage of the variant IL-10 ATA haplotype [Multivariable Odds Ratio (MOR) 1.9, P = 0.05)] and MBL2 codon 54Asp (MOR 2.0, P = 0.04) were independently associated with histologic chorioamnionitis, while homozygosity for the variant transforming growth factor beta-1 (TGFB1)-800G/-509T (GT) haplotype (MOR 0.2, P = 0.04), and carriage of TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) remained negatively associated with histologic chorioamnionitis
Summary
This case-control study was approved by the Women's and Children's Hospital Ethics and Research Committee. 181 women with a history of spontaneous preterm labour and subsequent PTB between 20 and 35 weeks in the index pregnancy had histological examination of the placenta performed. The definition of acute chorioamnionitis included funisitis and/or amnionitis In both groups a number of women had PPROM, occasional bleeding during pregnancy, recorded clinical chorioamnionitis or a history of prior term births. For PCR haplotyping combinations of forward and reverse allele-specific-primers were used to directly amplify alleles on the same chromosome [20] This technique provides a degree of redundancy, in that multiple reactions genotype a polymorphism, confirming results. Selection of genotype/haplotype for the model was based on strength of association, the previously reported importance of a gene variant and homozygosity of alleles. Breslow-Gehan Chi square was used to weight each gestational period by the total number at risk at that time so that earlier gestations receive greater weight than later gestations
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