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

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

Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex® Growth Forum Database Experience.

BACKGROUND/AIMS: We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children. METHODS: Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013. RESULTS: Mean ± SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 ± 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naïve to treatment, this was 7.3 ± 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%). CONCLUSION: Safety and effectiveness data on use of rhIGF-1 in a 'real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia

Kopplung zwischen biochemischen markergenen und leistungseigenschaften beim Braunvieh

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Relationship between cow fertility and milk progesterone

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