Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes ($\textit{ITGA4 }$ and $\textit{ITGB8}$) and at previously implicated loci ($\textit{ITGAL }$and $\textit{ICAM1}$). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, $\textit{PLCG2}$, and a negative regulator of inflammation, $\textit{SLAMF8}$. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.This work was co-funded by the Wellcome Trust [098051] and the Medical Research Council, UK [MR/J00314X/1]. Case collections were supported by Crohn’s and Colitis UK. KMdL, LM, CAL, YL, DR, JG-A, NJP, CAA and JCB are supported by the Wellcome Trust [098051; 093885/Z/10/Z; 094491/Z/10/Z]. KMdL is supported by a Woolf Fisher Trust scholarship. CAL is a clinical lecturer funded by the NIHR. We thank Anna Stanton for co-ordinating the Guy’s and St Thomas’ patient recruitment. We acknowledge support from the Department of Health via the NIHR comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and to Addenbrooke’s Hospital, Cambridge in partnership with the University of Cambridge. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council

The point placement problem on a line improved bounds for pairwise distance queries

This research is supported by the RGC grant HKU7119/05E.In this paper, we study the adaptive version of the point placement problem on a line, which is motivated by a DNA mapping problem. To identify the relative positions of n distinct points on a straight line, we are allowed to ask queries of pairwise distances of the points in rounds. The problem is to find the number of queries required to determine a unique solution for the positions of the points up to translation and reflection. We improved the bounds for several cases. We show that An/3 + O(√n) queries are sufficient for the case of two rounds while the best known result was 3n/2 queries. For unlimited number of rounds, the best result was 4n/3 queries. We obtain a much better result of using 5n/4 + O(√n) queries with three rounds only. We also improved the lower bound of 30n/29 to 17n/16 for the case of two rounds. © Springer-Verlag Berlin Heidelberg 2007.link_to_subscribed_fulltex

Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain

The prevalence of “vertebral endplate signal changes” (VESC) and its association with low back pain (LBP) varies greatly between studies. This wide range in reported prevalence rates and associations with LBP could be explained by differences in the definitions of VESC, LBP, or study sample. The objectives of this systematic critical review were to investigate the current literature in relation to the prevalence of VESC (including Modic changes) and the association with non-specific low back pain (LBP). The MEDLINE, EMBASE, and SveMED databases were searched for the period 1984 to November 2007. Included were the articles that reported the prevalence of VESC in non-LBP, general, working, and clinical populations. Included were also articles that investigated the association between VESC and LBP. Articles on specific LBP conditions were excluded. A checklist including items related to the research questions and overall quality of the articles was used for data collection and quality assessment. The reported prevalence rates were studied in relation to mean age, gender, study sample, year of publication, country of study, and quality score. To estimate the association between VESC and LBP, 2 × 2 tables were created to calculate the exact odds ratio (OR) with 95% confidence intervals. Eighty-two study samples from 77 original articles were identified and included in the analysis. The median of the reported prevalence rates for any type of VESC was 43% in patients with non-specific LBP and/or sciatica and 6% in non-clinical populations. The prevalence was positively associated with age and was negatively associated with the overall quality of the studies. A positive association between VESC and non-specific LBP was found in seven of ten studies from the general, working, and clinical populations with ORs from 2.0 to 19.9. This systematic review shows that VESC is a common MRI-finding in patients with non-specific LBP and is associated with pain. However, it should be noted that VESC may be present in individuals without LBP