RT Journal Article
T1 Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.
A1 Borghini, Lisa
A1 Png, Eileen
A1 Binder, Alexander
A1 Wright, Victoria J
A1 Pinnock, Ellie
A1 de Groot, Ronald
A1 Hazelzet, Jan
A1 Emonts, Marieke
A1 Van der Flier, Michiel
A1 Schlapbach, Luregn J
A1 Anderson, Suzanne
A1 Secka, Fatou
A1 Salas, Antonio
A1 Fink, Colin
A1 Carrol, Enitan D
A1 Pollard, Andrew J
A1 Coin, Lachlan J
A1 Kuijpers, Taco W
A1 Martinon-Torres, Federico
A1 Zenz, Werner
A1 Levin, Michael
A1 Hibberd, Martin L
A1 Davila, Sonia
A1 EUCLIDS consortium, 
AB Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
YR 2019
FD 2019-05-06
LK https://hdl.handle.net/10668/24612
UL https://hdl.handle.net/10668/24612
LA en
DS RISalud
RD Apr 17, 2025