Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Abstract

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.

Recurrent invasive meningococcal infections – quantifying the risk, Germany, 2002 to 2018

“…As complement deficiencies are inherited as an autosomal codominant trait [5], it would be reasonable to screen family members of IMD patients with confirmed complement deficiencies. Molecular data of IMD patients in the recent years have shown genetic predispositions inside and outside the complement system [8,9]. The relevance of these findings for the prevention of recurrent IMD has yet to be determined.…”

“…It is known that the prevalence of complement deficiencies is especially high in patients with recurrent IMD [5][6][7] but there are also reports of recurrent IMD associated with Waldenström's disease [2], chronic glomerulonephritis [3] and IgG2-subclass deficiency [4]. Host predisposition inside and outside the complement system seems to play an important role in the aetiology of IMD [8,9].…”

Detectable A Disintegrin and Metalloproteinase With Thrombospondin Motifs-1 in Serum Is Associated With Adverse Outcome in Pediatric Sepsis

“…Motifs-1 protein; bacterial infections; biomarkers; inflammation; mortality; sepsis P revalence and outcome of bacterial infections are determined by host (e.g., genetic predisposition, immune response to bacteria), pathogen, and healthcare system factors (1). The EUropean Childhood Lifethreatening Infectious Diseases Study (EUCLIDS) aims to identify genetic factors and biological pathways associated with susceptibility and/or severity of life-threatening bacterial infections (2)(3)(4). Preliminary EUCLIDS genetic studies in meningococcal sepsis patients identified a SNP in A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 (ADAMTS-1; rs9975310) to be associated with disease severity, although this association did not reach genome-wide significance (unpublished data).…”

RNA-Seq Data-Mining Allows the Discovery of Two Long Non-Coding RNA Biomarkers of Viral Infection in Humans

“…Recently, several studies have been exploring host-specific transcriptomic biomarkers that may allow distinguishing between viral and bacterial infections or pathogen-specific signatures [9][10][11][12][13][14][15][16]. Related to transcriptional signatures, there are also several studies relating host genetic susceptibility factors to infectious diseases [17][18][19][20][21].…”