1. Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q
- Author
-
Kjetil Klepper, Rigmor Austgulen, Linda Tømmerdal Roten, John Blangero, Eric K. Moses, Lawrence J. Abraham, Christine East, Per Arne Aas, Shaun P. Brennecke, Siri Forsmo, Matthew P. Johnson, and Mona H. Fenstad
- Subjects
medicine.medical_specialty ,Positional candidate ,lcsh:Medicine ,Obstetrics/Hypertensive Disorders ,Single-nucleotide polymorphism ,Locus (genetics) ,Susceptibility gene ,Computational biology ,Biology ,Genetics and Genomics/Complex Traits ,Polymorphism, Single Nucleotide ,White People ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pre-Eclampsia ,Pregnancy ,Molecular genetics ,Genetic variation ,B-Cell Activating Factor ,medicine ,Humans ,Genetic Predisposition to Disease ,Immunology/Reproductive Immunology ,Allele ,Obstetrics/Pregnancy ,lcsh:Science ,030304 developmental biology ,Genetics ,0303 health sciences ,030219 obstetrics & reproductive medicine ,Multidisciplinary ,Chromosomes, Human, Pair 13 ,Norway ,lcsh:R ,Australia ,Genetic Variation ,Creative commons ,3. Good health ,Case-Control Studies ,lcsh:Q ,Female ,Genetics and Genomics/Genetics of the Immune System ,Research Article - Abstract
Background: Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. Methodology/Principal Findings: The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/ control cohort (The Nord-Trøndelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women). Conclusion/Significance: TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia pathogenesis, and propose the rs16972194 variant as a candidate for further functional evaluation. © 2010 Fenstad et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Published
- 2010