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

Improving word reading speed: Individual differences interact with a training focus on successes or failures

Contains fulltext : 101028.pdf (publisher's version ) (Open Access) Contains fulltext : 101028-erratum.pdf (publisher's version ) (Open Access)The effect of two training procedures on the development of reading speed in poor readers is examined. One training concentrates on the words the children read correctly (successes), the other on the words they read incorrectly (failures). Children were either informed or not informed about the training focus. A randomized controlled trial was conducted with 79 poor readers. They repeatedly read regularly spelled Dutch consonant–vowel–consonant words, some children their successes, others their failures. The training used a computerized flashcards format. The exposure duration of the words was varied to maintain an accuracy rate at a constant level. Reading speed improved and transferred to untrained, orthographically more complex words. These transfer effects were characterized by an Aptitude-Treatment Interaction. Poor readers with a low initial reading level improved most in the training focused on successes. For poor readers with a high initial reading level, however, it appeared to be more profitable to practice with their failures. Informing students about the focus of the training positively affected training: The exposure duration needed for children informed about the focus of the training decreased more than for children who were not informed. This study suggests that neither of the two interventions is superior to the other in general. Rather, the improvement of general reading speed in a transparent orthography is closely related to both the children’s initial reading level and the type of words they practice with: common and familiar words when training their successes and uncommon and less familiar words with training their failures.29 p