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Multipotential hematopoietic stem cells differentiate into a wide variety of immune cells with a diversity of functions, including the ability to respond to a variety of stimuli. Importantly, numerous studies have demonstrated the importance of gene transcription in defining cell identity and functions. While these studies have primarily been performed at the level of the gene, it is known that key immune genes such as CD44 and CD45 generate multiple different transcripts that are differentially expressed across different immune cells, and that encode proteins with different sequences and functions. Prior genomic surveys have shown that the mechanisms for generating diversity in expressed transcripts (alternate splicing, alternate transcription start sites, etc.) are very active in immune cells, but have been lacking in terms of identifying genes with multiple transcripts, that are differentially expressed, and likely to affect cell functions.We first identified the set of genes that had at least two transcripts expressed in our RNA sequencing dataset generated from purified populations of neutrophils, monocytes and five lymphocyte populations (B, NK, γδ T, CD4 + T and CD8 + T) from twelve healthy donors. Next, we developed a heuristic approach to identify genes where two or more transcripts have distinct expression patterns across lymphoid and/or myeloid populations. We then focused our annotation and interpretation on differentially expressed transcripts that affect the coding sequence. This process was repeated to identify transcripts that were differentially expressed between monocytes and populations of macrophages and LPS-stimulated macrophages derived from these monocytes in vitro.We found that over 55 % of genes had two or more expressed transcripts, with an average ∼3 transcripts per gene, and that 70 % of these had at least two of the transcripts that encoded proteins with different sequences. As expected, we identified a complex pattern of differential expression for multiple transcripts encoding the CD45 transmembrane protein, but we also found similar evidence for ten other genes (CD300A, FYB1, GPI, LITAF, PSMA1, PTMA, RPL32, SEPTIN9, SH3BP2, SH3KBP1) when comparing the expression patterns of transcripts within myeloid and lymphoid cells. We also identified five genes with differentially expressed transcripts associated with the transition from monocytes to macrophages (FNBP1, KLF6, and SEPTIN9) or between macrophages and LPS-stimulated macrophages (CD44, OAZ2, and SEPTIN9). For the most part, we found that the different transcripts of these genes are expected to impact specific biological functions, for example the different transcripts of SEPTIN9 likely regulate the cytoskeleton in immune cells via their interactions with actins filaments and microtubules.This analytic approach successfully identified multi-transcript genes that are differentially expressed across immune cells and could be applied to other transcriptomic data.Researchers can request access to the individual-level data from the current study by contacting the Montreal Heart Institute ethics committee at the following institutional email address: cer.icm@icm-mhi.org.

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn’s disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing–dependent fashion. Furthermore, there were detrimental consequences for IBD patient–derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.

SummaryAltered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully dampened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched PicornovirusEnterovirus B,not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential.One Sentence SummaryHuman viromes divergently shape host immunity and disease

Background Genome wide association studies (GWAS) have identified and validated more than 200 genomic loci associated with the inflammatory bowel disease (IBD), although for most the causal gene remains unknown. Given the importance of myeloid cells in IBD pathogenesis, the current study aimed to uncover the role of genes within IBD genetic loci that are endogenously expressed in this cell lineage. Methods The open reading frames (ORF) of 42 genes from IBD-associated loci were expressed via lentiviral transfer in the THP-1 model of human monocytes and the impact of each of these on the cell’s transcriptome was analyzed using a RNA sequencing-based approach. We used a combination of genetic and pharmacologic approaches to validate our findings in the THP-1 line with further validation in human induced pluripotent stem cell (hiPSC)-derived-monocytes. Results This functional genomics screen provided evidence that genes in four IBD GWAS loci (PTGIR, ZBTB40, SLC39A11 and NFKB1) are involved in controlling S100A8 and S100A9 gene expression, which encode the two subunits of calprotectin (CP). We demonstrated that increasing PTGIR expression and/or stimulating PTGIR signaling resulted in increased CP expression in THP-1. This was further validated in hiPSC-derived monocytes. Conversely, knocking-down PTGIR endogenous expression and/or inhibiting PTGIR signaling led to decreased CP expression. These analyses were extended to the known IBD gene PTGER4, whereby its specific agonist also led to increased CP expression. Furthermore, we demonstrated that the PTGIR and PTGER4 mediated control of CP expression was dependent on signaling via adenylate cyclase and STAT3. Finally, we demonstrated that LPS-mediated increases in CP expression could be potentiated by agonists of PTGIR and PTGER4, and diminished by their antagonists. Conclusion Our results support a causal role for the PTGIR, PTGER4, ZBTB40, SLC39A11 and NFKB1 genes in IBD, with all five genes regulating the expression of CP in myeloid cells, as well as potential roles for the prostacyclin/prostaglandin biogenesis and signaling pathways in IBD susceptibility and pathogenesis.

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequenced data from more than 30,000 CD patients and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic "reader," and SP140 loss-of-function mutations associate with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) result in chronic inflammation of the gastrointestinal tract. Genetic studies have shown that the GPR65 gene, as well as its missense coding variant, GPR65*Ile231Leu, is associated with IBD. We aimed to define the signalling and biological pathways downstream of GPR65 activation and evaluate the impact of GPR65*231Leu on these. METHODS: We used HEK 293 cells stably expressing GPR65 and deficient for either Gα(s), Gα(q/11) or Gα(12/13), to define GPR65 signalling pathways, IBD patient biopsies and a panel of human tissues, primary immune cells and cell lines to determine biologic context, and genetic modulation of human THP-1-derived macrophages to examine the impact of GPR65 in bacterial phagocytosis and NLRP3 inflammasome activation. RESULTS: We confirmed that GPR65 signals via the Gα(s) pathway, leading to cAMP accumulation. GPR65 can also signal via the Gα(12/13) pathway leading to formation of stress fibers, actin remodelling and RhoA activation; all impaired by the IBD-associated GPR65*231Leu allele. Gene expression profiling revealed greater expression of GPR65 in biopsies from inflamed compared to non-inflamed tissues from IBD patients or control individuals, potentially explained by infiltration of inflammatory immune cells. Decreased GPR65 expression in THP-1-derived macrophages leads to impaired bacterial phagocytosis, increased NLRP3 inflammasome activation and IL-1β secretion in response to an inflammatory stimulus. CONCLUSIONS: We demonstrate that GPR65 exerts its effects through Gα(s)- and Gα(12/13)-mediated pathways, that the IBD-associated GPR65*231Leu allele has compromised interactions with Gα(12/13) and that KD of GPR65 leads to impaired bacterial phagocytosis and increased inflammatory signaling via the NLRP3 inflammasome. This work identifies a target for development of small molecule therapies.

Genome-wide transcriptomic analyses have provided valuable insight into fundamental biology and disease pathophysiology. Many studies have taken advantage of the correlation in the expression patterns of the transcriptome to infer potential biologic function of uncharacterized genes and multiple groups have examined the relationship between co-expression, co-regulation, and gene function on a broader scale. Given the unique characteristics of immune cells circulating in blood, we were interested in determining whether it was possible to identify functional co-expression modules in human immune cells. Specifically, we sequenced the transcriptome of nine immune cell types from peripheral blood cells of healthy donors and, using a combination of global and targeted analyses of genes within co-expression modules, we were able to determine functions for these modules that were cell lineage specific or shared among multiple cell lineages. In addition, our analyses identified transcription factors likely important for immune cell lineage commitment and/or maintenance.

BackgroundSudden cardiac death (SCD) accounts for ~300,000 deaths annually in the US. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease (CAD) than women. In contrast, women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the underlying genetics of QT interval duration. Using sex- and CAD-stratified analyses, we assess differences in genetic association between prolonged QT interval and SCD risk.MethodsWe examined 2,282 SCD subjects with autopsy-confirmed underlying disease from the Fingesture cohort and 3,561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic vs. non-ischemic) and by sex. We used logistic regression to test for association between the top QT interval associated SNP, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups.ResultsFemale SCD victims with underlying non-ischemic disease had the strongest association between rs12143842 and SCD risk (OR=1.37; 95% CI, 1.07-1.75) and the strongest causal association, established using Mendelian randomization, between prolonged QT interval and SCD (OR in SCD risk per SD increase in QT, 3.60; 95% CI, 1.22-10.49). Ischemic SCD victims, irrespective of sex, did not show an association between rs12143842 and SCD risk or a causal association for QT interval.ConclusionsThis study provides evidence that the causal effect of QT prolongation on SCD risk differs by sex and underlying disease.

Background Ventricular arrhythmias and sudden cardiac deaths are among the leading causes of mortality in patients with heart failure, and the underlying mechanisms remain incompletely understood. Chronic elevation of angiotensin II (ANGII) is known to be one of the main contributors to heart failure. Objective We tested whether ANGII can alter ventricular conduction and Na + current using transgenic mice with cardiomyocyte-restricted overexpression of ANGII type 1 receptor (AT1R). Methods We used surface electrocardiograms along with current- and voltage-clamp techniques to characterize the electrophysiological properties of AT1R mice while the underlying regulatory mechanisms were explored using reverse transcription/quantitative polymerase chain reaction, Western blots, and immunofluorescence techniques. Results Electrophysiological data indicated that chronic AT1R activation in ventricular myocytes caused a 60% reduction in Na + current density that slowed the maximal velocity of the action potential upstroke, leading to a prolongation of the QRS complex. These changes occur independently of cardiac hypertrophy, suggesting a direct role for ANGII/AT1R in slowing ventricular conduction. Western blots demonstrated a selective increase in sarcolemmal protein kinase Cα (PKCα) in AT1R mice, indicating PKCα activation. Furthermore, immunofluorescence analysis showed reorganization of PKCα expression to sarcolemma and colocalization with Na V 1.5 in AT1R myocytes. The involvement of PKCα in regulating Na + current was subsequently demonstrated in human-induced pluripotent stem cell–derived cardiomyocytes where ANGII treatment reduced Na + current density. Concomitant treatment with αV5-3, a PKCα translocation inhibitor peptide, blocked the ANGII effect. Conclusion Overall, this study suggests that in mouse and human cardiomyocytes, PKCα is an important mediator of the ANGII-induced reduction in Na + current and may contribute to ventricular arrhythmias.

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Inflammatory bowel disease (IBD) are chronic inflammatory diseases including Crohn’s disease (CD) and ulcerative colitis (UC). More than 200 genomic regions have been identified and validated (association values〈 5x10-8) to be associated with CD, UC or IBD. These regions may contain multiple genes and the current challenge lies in identifying the causal gene in each of these. To address this problem, we performed a functional genomic screen of 145 genes from validated IBD loci, in a relevant intestinal epithelial cell model (HT-29). The results of this transcriptome-based screening revealed that the candidate IBD gene DUSP16 (a dual specificity phosphatase targeting MAP kinases (MAPKs) phosphorylation) as well as the known IBD gene KSR1 (a scaffold protein regulating the spatiotemporal activation of the ERK) regulate the expression of genes involved in intestinal differentiation and homeostasis. They induce, among others, the expression of the PIGR gene that encodes the polymeric immunoglobulin receptor. PIGR plays a role in transporting dimeric IgA molecules from the basolateral membrane of epithelial cells to the intestinal lumen, via transcytosis, where they play an essential role in protecting the epithelium against intestinal pathogens. Our hypothesis is that DUSP16 and KSR1 modulate the activity of MAPKs in intestinal epithelial cells to induce PIGR expression, thus participating in the maintenance of homeostasis of the intestinal barrier. To better understand how DUSP16 modulates the expression of PIGR, we used an approach of over- expression (cDNA) and knockdown (shRNA) of DUSP16 in HT-29 cells. Our results confirmed that DUSP16 induction increases the expression of PIGR, whereas a knockdown of DUSP16 reduces the basal level of PIGR. Next we confirmed by Western Blot that the induction of DUSP16 was accompanied by a decrease in MAPK phosphorylation. The involvement of MAPKs was also confirmed through the use of chemical inhibitors specific for each MAPK, with inhibition of ERK and p38 showing the strongest induction of PIGR expression. We are currently analyzing known functional mutants of DUSP16 and KSR1 to determine their impact on MAPK activity and on PIGR expression. This work supports a role for PIGR in disease pathogenesis, adding to two recent studies that documented that patients suffering from UC accumulated somatic mutations in a group of genes regulating the expression of PIGR by Interleukin 17. The mutated genes, including PIGR, were positively selected in inflamed tissues, indicating the importance of the biological function occupied by this gene in the maintenance of homeostasis. In conclusion, our study successfully identified functional links between two genes from independent IBD loci, and suggests that these DUSP16 and KSR1 play a role in the process of epithelial transcytosis and the development of IBD.

Background Sudden cardiac death ( SCD ) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex‐ and coronary artery disease–stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval–associated single‐nucleotide polymorphism, rs12143842 (in the NOS 1 AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non‐ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate ( P =0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.

Background— Long-QT syndrome is a potentially fatal condition for which 30% of patients are without a genetically confirmed diagnosis. Rapid identification of causal mutations is thus a priority to avoid at-risk situations that can lead to fatal cardiac events. Massively parallel sequencing technologies are useful for the identification of sequence variants; however, electrophysiological testing of newly identified variants is crucial to demonstrate causality. Long-QT syndrome could, therefore, benefit from having a standardized platform for functional characterization of candidate variants in the physiological context of human cardiomyocytes. Methods and Results— Using a variant in Kir2.1 (Gly52Val) revealed by whole-exome sequencing in a patient presenting with symptoms of long-QT syndrome as a proof of principle, we demonstrated that commercially available human induced pluripotent stem cell–derived cardiomyocytes are a powerful model for screening variants involved in genetic cardiac diseases. Immunohistochemistry experiments and whole-cell current recordings in human embryonic kidney cells expressing the wild-type or the mutant Kir2.1 demonstrated that Kir2.1-52V alters channel cellular trafficking and fails to form a functional channel. Using human induced pluripotent stem cell–derived cardiomyocytes, we not only confirmed these results but also further demonstrated that Kir2.1-52V is associated with a dramatic prolongation of action potential duration with evidence of arrhythmic activity, parameters which could not have been studied using human embryonic kidney cells. Conclusions— Our study confirms the pathogenicity of Kir2.1-52V in 1 patient with long-QT syndrome and also supports the use of isogenic human induced pluripotent stem cell–derived cardiomyocytes as a physiologically relevant model for the screening of variants of unknown function.

Microsatellite market requires high performance while minimizing mass, volume and cost. Telescopes are specifically targeted by these trade-offs. One of these is to use the optomechanical structure of the telescope to mount electronic devices that may dissipate heat. However, such approach may be problematic in terms of distortions due to the presence of high thermal gradients throughout the telescope structure. To prevent thermal distortions, Carbon Fiber Reinforced Polymer (CFRP) technology can be used for the optomechanical telescope material structure. CFRP is typically about 100 times less sensitive to thermal gradients and its coefficient of thermal expansion (CTE) is about 200 to 600 times lower than standard aluminum alloys according to inhouse measurements. Unfortunately, designing with CFRP material is not as straightforward as with metallic materials. There are many parameters to consider in order to reach the desired dimensional stability under thermal, moisture and vibration exposures. Designing optomechanical structures using CFRP involves many challenges such as interfacing with optics and sometimes dealing with high CTE mounting interface structures like aluminum spacecraft buses. INO has designed a CFRP sandwich telescope structure to demonstrate the achievable performances of such technology. Critical parameters have been optimized to maximize the dimensional stability while meeting the stringent environmental requirements that microsatellite payloads have to comply with. The telescope structure has been tested in vacuum from -40°C to +50°C and has shown a good fit with finite element analysis predictions.

Item does not contain fulltext More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximately 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. 01 november 2011

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.

We conducted a search for protein truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. We found that a protein truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF = up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P = 6.89×10-7, odds ratio (OR) = 0.30). We further demonstrate that the truncated protein is expressed, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization or loss of an essential protein element.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder that affects millions worldwide. Genome-wide association studies (GWAS) have identified 200 IBD-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 IBD loci using high-density genotyping in 67,852 individuals. Of the 139 independent associations identified in these regions, 18 were pinpointed to a single causal variant with >95% certainty, and an additional 27 associations to a single variant with >50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription factor binding sites (n=3) and tissue specific epigenetic marks (n=10), with the latter category showing enrichment in specific immune cells among associations stronger in CD and gut mucosa among associations stronger in UC. The results of this study suggest that high-resolution, fine-mapping in large samples can convert many GWAS discoveries into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

All-trans retinoic acid (RA), the principle biologically active form of vitamin A, is essential for many developmental process as well as homeostasis in the adult. Many lines of evidence also suggest that RA, acting through the RA receptors (RARs), can also suppress growth of tumors of diverse origin. To assess directly the role of the RARs in a model of epidermal tumorigenesis, we investigated the incidence of tumor formation using keratinocytes lacking specific RAR types. Our data suggest that loss of RARgamma, but not RARalpha, predisposed keratinocytes to v-Ha-Ras-induced squamous cell carcinoma. We also found that ablation of RARgamma, but not RARalpha, abolished RA-induced cell cycle arrest and apoptosis in these keratinocytes. Reconstitution of receptor expression into RAR-null cells restored sensitivity to RA, and reversed the tumorigenic potential of receptor-deficient keratinocytes. These data strongly support a tumor suppressor effect for the RARs, in particular endogenous RARgamma, in murine keratinocytes.

Wavefront sensing is one of the key elements of an Adaptive Optics System. Although Shack-Hartmann WFS are the most commonly used whether for astronomical or biomedical applications, the high-sensitivity and large dynamic-range of the Pyramid-WFS (P-WFS) technology is promising and needs to be further investigated for proper justification in future Extremely Large Telescopes (ELT) applications. At INO, center for applied research in optics and technology transfer in Quebec City, Canada, we have recently set to develop a Pyramid wavefront sensor (P-WFS), an option for which no other research group in Canada had any experience. A first version had been built and tested in 2013 in collaboration with NRC-HIA Victoria. Here we present a second iteration of demonstrator with an extended spectral range, fast modulation capability and low-noise, fast-acquisition EMCCD sensor. The system has been designed with compactness and robustness in mind to allow on-sky testing at Mont Megantic facility, in parallel with a Shack- Hartmann sensor so as to compare both options.

BACKGROUND There is limited information on genetic factors OBJECTIVE To assess the association of common variation in associated with sudden cardiac arrest (SCA). genes in fatty acid pathways with SCA risk. METHODS We selected 85 candidate genes and 1155 single nucleotide poLymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used Linear Logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of

Retinoids are essential for normal epidermal growth and differentiation and show potential for the prevention or treatment of various epithelial neoplasms. The retinoic acid receptors (RARalpha, -beta, and -gamma) are transducers of the retinoid signal. The epidermis expresses RARgamma and RARalpha, both of which are potential mediators of the effects of retinoids in the epidermis. To further investigate the role(s) of these receptors, we derived transformed keratinocyte lines from wild-type, RARalpha, RARgamma, and RARalphagamma null mice and investigated their response to retinoids, including growth inhibition, markers of growth and differentiation, and AP-1 activity. Our results indicate that RARgamma is the principle receptor contributing to all-trans-retinoic acid (RA)-mediated growth arrest in this system. This effect partially correlated with inhibition of AP-1 activity. In the absence of RARs, the synthetic retinoid N-(4-hydroxyphenyl)-retinamide inhibited growth; this was not observed with RA, 9-cis RA, or the synthetic retinoid (E)-4-[2-(5, 5, 8, 8 tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl] benzoic acid. Finally, both RARalpha and RARgamma differently affected the expression of some genes, suggesting both specific and overlapping roles for the RARs in keratinocytes.

Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for homocysteine remethylation to methionine. Severe MTHFR deficiency is associated with hyperhomocysteinemia and homocystinuria. These patients show a wide variety of neurological and vascular symptoms, with variable age of onset. Residual enzyme activity is usually less than 20% of control values, and correlates reasonably well with age of onset of symptoms. A milder deficiency of MTHFR, with 30%-50% residual enzyme activity and increased enzyme thermolability, has been described as a risk factor for vascular disease and for neural tube defects. In earlier work, we isolated the human cDNA for MTHFR, and reported 14 mutations in severe MTHFR deficiency, as well as a common 677C-->T missense mutation (Ala-->Val) that encodes the thermolabile MTHFR. This variant has also been observed in some patients with severe MTHFR deficiency, in cis with their severe mutations. We report here the in vitro expression of seven severe MTHFR mutations in a bacterial expression system; six of these were expressed in cis with the Val allele to mimic the situation in the patients. We show that three of these constructs have significantly reduced enzyme activity (

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A human cDNA for MTHFR, 2.2 kb in length, has been expressed and shown to result in a catalytically active enzyme of approximately 70 kDa. Fifteen mutations have been identified in the MTHFR gene: 14 rare mutations associated with severe enzymatic deficiency and 1 common variant associated with a milder deficiency. The common polymorphism has been implicated in three multifactorial diseases: occlusive vascular disease, neural tube defects, and colon cancer. The human gene has been mapped to chromosomal region 1p36.3 while the mouse gene has been localized to distal Chromosome (Chr) 4. Here we report the isolation and characterization of the human and mouse genes for MTHFR. A human genomic clone (17 kb) was found to contain the entire cDNA sequence of 2.2 kb; there were 11 exons ranging in size from 102 bp to 432 bp. Intron sizes ranged from 250 bp to 1.5 kb with one exception of 4.2 kb. The mouse genomic clones (19 kb) start 7 kb 5' exon 1 and extend to the end of the coding sequence. The mouse amino acid sequence is approximately 90% identical to the corresponding human sequence. The exon sizes, locations of intronic boundaries, and intron sizes are also quite similar between the two species. The availability of human genomic clones has been useful in designing primers for exon amplification and mutation detection. The mouse genomic clones will be helpful in designing constructs for gene targeting and generation of mouse models for MTHFR deficiency.

In carbon fiber reinforced plastic (CFRP) optomechanical structures, particularly when embodying reflective optics, angular stability is critical. Angular stability or warping stability is greatly affected by moisture absorption and thermal gradients. Unfortunately, it is impossible to achieve the perfect laminate and there will always be manufacturing errors in trying to reach a quasi-iso laminate. Some errors, such as those related to the angular position of each ply and the facesheet parallelism (for a bench) can be easily monitored in order to control the stability more adequately. This paper presents warping experiments and finite-element analyses (FEA) obtained from typical optomechanical sandwich structures. Experiments were done using a thermal vacuum chamber to cycle the structures from −40°C to 50°C. Moisture desorption tests were also performed for a number of specific configurations. The selected composite material for the study is the unidirectional prepreg from Tencate M55J/TC410. M55J is a high modulus fiber and TC410 is a new-generation cyanate ester designed for dimensionally stable optical benches. In the studied cases, the main contributors were found to be: the ply angular errors, laminate in-plane parallelism (between 0° ply direction of both facesheets), fiber volume fraction tolerance and joints. Final results show that some tested configurations demonstrated good warping stability. FEA and measurements are in good agreement despite the fact that some defects or fabrication errors remain unpredictable. Design guidelines to maximize the warping stability by taking into account the main dimensional stability contributors, the bench geometry and the optical mount interface are then proposed.

Methionine synthase catalyzes the remethylation of homocysteine to methionine in a methylcobalamin-dependent reaction. We used specific regions of homology within the methionine synthase sequences of several lower organisms to clone a human methionine synthase cDNA by a combination of RT-PCR and inverse PCR. The enzyme is 1265 amino acids in length and contains the seven residue structure-based sequence fingerprint identified for cobalamin-containing enzymes. The gene was localized to chromosome 1q43 by the FISH technique. We have identified one missense mutation and a 3 bp deletion in patients of the cblG complementation group of inherited homocysteine/folate disorders by SSCP and sequence analysis, as well as an amino acid substitution present in high frequency in the general population. We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) presumably caused by dysregulated immune responses to the gut microbiota. Genetic association studies have implicated dozens of chromosomal regions or loci in IBD susceptibility. The next challenge is to explain the individual role of each of these modest effect loci in the disease state. We have previously identified MAST3 as an IBD susceptibility gene through genetic fine-mapping of the 19p linkage region. Testing MAST3 in a reporter assay provided preliminary evidence that MAST3 modulates the activity of inflammation-related transcription factor nuclear factor kappa B.Here we characterized the function of MAST3 through an examination of the influence of the modulation of MAST3 expression on endogenous genome-wide expression patterns. More specifically, we looked at differential gene expression resulting from overexpression and knockdown of the MAST3 gene in epithelial and macrophage cell lines. From we highlight a group of genes whose expression is modulated by MAST3 and correlate their expression with NF-jB activity. Their expression was found to be enriched in inflamed mucosal tissue of UC patients, confirming the importance of these genes in IBD.We highlight a group of genes whose expression is modulated by MAST3 and correlate their expression with NF-κB activity. Their expression was found to be enriched in inflamed mucosal tissue of UC patients, confirming the importance of these genes in IBD. These MAST3-regulated genes are central to mucosal immune responses. Among them are proinflammatory cytokines (e.g., CCL20, IL8), regulators of NF-κB (e.g., TNFAIP3, LY96, NFKBIA), genes involved in interferon-induced defense against pathogen invasion (e.g., IFIT1, ISG15), and genes involved in cell adhesion and/or migration (e.g., CD44, TMOD1).Taken together, these results confirm MAST3 as a modulator of the inflammatory response through regulation of immune gene expression in the gut of IBD patients.

The IBD5 locus is a genetic risk factor for IBD, particularly Crohn's Disease, coding for the organic cation/carnitine transporters (OCTN1 and 2). Two variants of OCTN are associated with susceptibility to Crohn's Disease. Modified transport of carnitine in vitro has been reported for a polymorphism of OCTN1. The aim was to investigate the function of intestinal OCTNs in IBD in relation to genetic polymorphisms.Intestinal tissue was obtained from endoscopic biopsies and surgical resections from IBD patients (n=33 and 14, resp.) and controls (n=22 and 14, resp.). OCTN protein levels were measured in intestinal biopsies and carnitine transport was quantified in intestinal resections.OCTN1 protein levels were significantly higher in ileal versus colonic tissue (2.95% ± 0.4 vs 0.66% ± 0.2, resp.; p0.0002). OCTN1 expression was higher in Crohn's disease patients with mutant homozygous or heterozygous genotypes (0.6% ± 0.1 vs 3% ± 0.8, resp., p0.02). Carnitine transport was very rapid and Na+ dependent (10s). It was not different comparing Crohn's Disease and control groups (0.45 ± 0.12 vs 0.51 ± 0.12 nM carnitine/mg prot/min, resp.). Carnitine transport tended to be higher in subjects with mutant homozygous and heterozygous OCTN1 and OCTN2 genotypes (0.19 vs 0.59 and 0.25 vs 0.6, respectively).The present data reveal that OCTN protein levels appear to be similar in intestinal tissue from Crohn's Disease patients and controls. Overall, ileal carnitine transport appears to as well equal in Crohn's Disease and control groups. However, there was a trend towards higher carnitine transport in subjects with OCTN1 and OCTN2 mutations.

BackgroundIn Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.Methodology/principal findingsA case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.ConclusionsA MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.

The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.

Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn’s disease (CD) is associated with SNPs around IRGM1,2, but coding-sequence variation has been excluded as a source of this association2. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.

Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major carbon donor in the remethylation of homocysteine to methionine. Mild MTHFR deficiency, due to a common variant at nucleotide 677, has been reported to alter risk for several disorders including cardiovascular disease, neural tube defects, pregnancy complications, and certain cancers. Little is known about MTHFR regulation, since the complete cDNA and gene sequences have not been determined. In earlier work, we isolated and expressed a 2.2-kb human cDNA comprised of 11 coding exons, and we demonstrated that it encoded an active 70-kDa isoform. However, transcript sizes of approximately 7.5 kb and 9.5 kb and the presence of a second isoform of 77 kDa on Western blots suggested that cDNA sequences were incomplete. In this report, we characterized the complete cDNA and gene structure in human and mouse. Variable 5? and 3? UTR regions were identified, resulting in transcript heterogeneity. The 5? and 3? termini of the MTHFR cDNA were found to overlap with the 5? terminus of a chloride ion channel gene (CLCN-6) and the 3? terminus of an unidentified gene, respectively; this finding has resulted in finer mapping of MTHFR on Chromosome (Chr) 1p36.3. Ribonuclease protection assays identified clusters of transcriptional start sites, suggesting the existence of multiple promoters. MTHFR has several polyadenylation sites creating 3?UTR lengths of 0.2 kb-5.0 kb or 0.6 kb-4.0 kb in human and mouse, respectively. In both species, the previously reported exon 1 was redefined to approximately 3.0 kb in length and shown to be alternatively spliced. An important splice variant contains novel coding sequences; this cDNA was expressed and shown to encode the isozyme of 77 kDa. Our results, which suggest intricate regulation of MTHFR, will facilitate additional regulatory and functional studies of the different isoforms.

Abstract Mild hyperhomocysteinemia, a risk factor for occlusive arterial disease, can be caused by disruptions of homocysteine metabolism. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for homocysteine remethylation to methionine. A common mutation in MTHFR , an alanine-to-valine substitution, may contribute to mild hyperhomocysteinemia in coronary artery disease (CAD). To test this hypothesis, we studied 152 patients with CAD by mutation analysis, MTHFR enzymatic assays, and measurements of plasma homocysteine and several vitamins. The MTHFR mutation was associated with reduced enzymatic activity and increased enzyme thermolability in these patients. The difference in the prevalence of the homozygous mutant genotype between the CAD patients (14%) and an unmatched group of healthy subjects (10%) was not significant. However, individuals with the homozygous mutant genotype had higher plasma homocysteine, particularly when plasma folate was below the median value. This genetic-environmental interaction is proposed to be a risk factor for CAD.

Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine methylation to methionine. MTHFR deficiency, an autosomal recessive disorder, results in homocysteinemia. Using degenerate oligonucleotides based on porcine peptide sequence data, we isolated a 90-bp cDNA by PCR from pig liver RNA. This cDNA was used to isolate a human cDNA, the predicted amino acid sequence of which shows strong homology to porcine MTHFR and to bacterial metF genes. The human gene has been localized to chromosome 1p36.3. Two mutations were identified in MTHFR-deficient patients: a missense mutation (Arg to Gln), in a residue conserved in bacterial enzymes, and a nonsense mutation (Arg to Ter).

Nat. Genet. 43, 246–252 (2011); published online 6 February 2011; corrected after print 11 August 2011 In the version of this article initially published, an affiliation was missing for two authors, Maria Gazouli and Nicholas P. Anagnou. They are also affiliated with the Foundation for Biomedical Research of the Academy of Athens in Athens, Greece.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)., Author Summary Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.

Genome-wide association identifies multiple ulcerative colitis susceptibility loci (vol 42, pg 332, 2010)

Nat. Genet. 41, 216–220 (2009), published online 4 January 2009; corrected after print 28 April 2009 In the first paragraph of the second column on the third page, rs11209026 A allele was incorrectly listed as rs111209026 A allele. The error has been corrected in the HTML and PDF versions of the article.