Molecular genetic analysis of the neurokinin B (TAC3) and neurokinin B receptor (TAC3) genes as candidates for pre-eclampsia

[摘要] ENGLISH ABSTRACT:Hypertensive conditions of pregnancy, such as pre-eclampsia, are the principal directcause of maternal morbidity and mortality and affect up to 10% of first pregnanciesworldwide. The placenta is vital in the pathogenesis of pre-eclampsia since thecondition only occurs in the presence of placental tissue and the only cure is deliveryof the placenta and the fetus. It has been hypothesised that the placenta may be thesource of a circulating factor(s), which transports freely in the maternal system,resulting in the multi-systemic and immunological responses that are characteristic ofpre-eclampsia. Among the potential circulating candidates currently beinginvestigated worldwide, is the tachykinin member, neurokinin B (NKB).The aim of this project was to use a novel approach and investigate the role ofNeurokinin B in pre-eclampsia on a genetic level. This would be achieved bybioinformatie characterisation of the neurokinin B (TAC3) and neurokinin B receptor(TACR3) genes. Samples from thirty pre-eclampsia patients (of whom 10 also hadabruptio placentae) and twenty control individuals were used for mutation detectionanalysis involving Multiphor gel electrophoresis and automated sequencing.Three sequence variants were identified in the TAC3 gene and include: (i) 5' UTRvariant (-25 c-t); (ii) intronic variant IVS3-53 (t-g) and (iii) 3' UTR variant exon 7(479, t-c). Only the -25 c-t variant had been reported before (SNP database). Afurther two variants were identified in the TACR3 gene: (i) exon 3 variant (nt 857, a-t)and (ii) 3' UTR variant, amplicon 5b (nt 1471, t-c), of which the latter had previouslybeen reported in the SNP database. In the analysis of allele and genotype frequencies,only variant homozygosity for TAC3 -25 c-t could be associated with increased riskof pre-eclampsia (RR 3.33, p=0.03). Follow-up work will include extendedgenotyping in further stratified and larger patient cohorts and transfection studies toassess splicing potential and functional consequences of the mutant alleles.These data represent the first documented mutation screen of the TAC3 and TACR3genes and report novel variants in patients with pre-eclampsia. This study contributesto the knowledge of neurokinin B as a circulatory molecule and confirms theheterogeneity of pre-eclampsia.

[发布机构] Stellenbosch University