Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

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

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Letter. Ceftriaxone drug alert: no longer for first line use in meningococcal sepsis.

Although UK and international high income country practice has been to recommend ceftriaxone or cefotaxime as first line therapy for the initial treatment of paediatric sepsis, the US FDA has issued an alert1 that has led to changes in the US label for ceftriaxone.2 Due to concerns regarding the potential for calcium chelation in vivo, ceftriaxone must no longer be administered within 48 h of the completion of infusions of calcium-containing solutions, including parenteral nutrition, regardless of whether the drugs are administered by different infusion catheters.1 2 In the UK, the current drug safety bulletin3 states that ceftriaxone must not be given simultaneously with calcium-containing infusions. We would therefore like to update the antibiotic recommendation made in our meningococcal therapy guideline update published in the April 2007 issue of ADC4 as follows: "Cefotaxime should be used as the first line antibiotic in meningococcal sepsis due to the high incidence of calcium replacement requirement in severe disease. However, ceftriaxone may still be considered as first line therapy in children with clinical meningitis, and for continuation of sepsis therapy after the acute phase when calcium infusions are no longer required. Where children are admitted for observation following cefotaxime for suspected sepsis and are subsequently assessed as being well enough for discharge on ambulatory intravenous antibiotics, the antibiotic may be changed to ceftriaxone (where the once/day dose regimen may be of benefit) and the first dose administered 8 hours following the last dose of cefotaxime given, assuming no calcium containing infusions have been used or are planned". The Meningitis Research Foundation will be making appropriate changes to their educational literature. <br/