Molecular genetic analysis of preterm labour

[摘要] ENGLISH ABSTRACT: The World Health Organisation (WHO) has defined preterm labour as the onset of labour before37 completed weeks of gestation with an incidence ranging between 5-10%. Although patientcare has improved, the rate of preterm birth has slowly been increasing and currently impactssignificantly on maternal and fetal mortality and morbidity. The complex condition of pretermlabour involves multiple etiologies and risk factors, which complicates the search for candidatemarkers and / or biomarkers.The aim of this prospective study was to investigate potential genetic associations with pretermlabour. The study cohort consisted of consecutive first-time booking, low-risk primigravidpregnant women from a restricted geographical region.The study cohort comprised 421 [306 Coloured and 115 Black] pregnant women presenting at thePaarl Hospital Obstetric clinic. Subsequently, DNA was extracted from whole blood andinvestigated for a range of known polymorphisms in pro-inflammatory and anti-inflammatorycytokines, as well as the novel LGALS13 gene, for potential variants that may impact onpregnancy outcome. Screening techniques involve combinations of allele-specific PCRamplification, Multiphor SSCP/HD analysis, restriction enzyme analyses and DNA sequencing.A significant association was demonstrated between the IL-1RN*2-allele and adverse pregnancyoutcome, mainly in the preterm labour and hypertension group. The presence TNFα-308 A-allelewas associated with overall adverse pregnancy outcome and preterm labour. In addition to this, anovel IL-1RN allele was identified in the control group.Mutation screening and subsequent statistical methods revealed an association between a novelLGALS13 exonic variant, 221delT, and preterm labour in Coloured women. Two previouslydocumentedintronic variants (IVS2-22A/G and IVS3+72T/A) demonstrated linkagedisequilibrium, signifying evolutionary conservation of exon three. Additionally, two novelintronic variants, IVS2-36 G/A and IVS2-15 G/A, demonstrated no association with adversepregnancy outcome. In this study we identified rare novel exonic variants; two non-synonymous variants in exon three(M44V, [N=2] and K87R, [N=1]) and a silent variant in exon four (P117P, [N=1]) - all identifiedin individuals from the control cohort. Within coding exon three, an interesting variant['hotspot] was identified, which represents six polymorphic bases within an 11bp stretch. Noassociations were demonstrated with these variants and pregnancy outcome.Furthermore, a previously documented 5' ''promoter variant, -98 A/C, was identified anddemonstrated no association with adverse pregnancy outcome. However, subdivision of lateonsetpre-eclamptic cases revealed a significant association with the A-allele and late-onset preeclampsia.Genotype-phenotype investigation demonstrated association between the IL-10 -1082 A/G, IL-4C/T and 221delT loci and poor pregnancy progress which manifested as (i) delivery of infantsweighing <2000g, (ii) before 37 weeks of gestation.The findings of this study will strengthen our understanding of the pathophysiology underlyingpregnancy complications and facilitate the further development of effective treatment strategies toreduce maternal and fetal morbidity and mortality.

[发布机构] Stellenbosch University