Exome-wide meta-analysis identifies rare 3'-UTR variant in ERCC1/CD3EAP associated with symptoms of sleep apnea

Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10-9, ßmeta = 0.99). Rs2229918 overlaps with the 3' untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

Background: Genetic tests for primary immunodeficiency disorders (PIDs) are expensive, time-consuming, and not easily accessible in developing countries. Therefore, we studied the feasibility of a customized single nucleotide variant (SNV) microarray that we developed to detect disease-causing variants and copy number variation (CNV) in patients with PIDs for only 40 Euros. Methods: Probes were custom-designed to genotype 9,415 variants of 277 PID-related genes, and were added to the genome-wide Illumina Global Screening Array (GSA). Data analysis of GSA was performed using Illumina GenomeStudio 2.0, Biodiscovery Nexus 10.0, and R-3.4.4 software. Validation of genotype calling was performed by comparing the GSA with whole-genome sequencing (WGS) data of 56 non-PID controls. DNA samples of 95 clinically diagnosed PID patients, of which 60 patients (63%) had a genetically established diagnosis (by Next-Generation Sequencing (NGS) PID panels or Sanger sequencing), w

Genetic variants in RBFOX3 are associated with sleep latency

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10-08, 6.59 × 10- 08 and 9.17 × 10- 08). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10- 02, 7.0 × 10- 03 and 2.5 × 10- 03; combined meta-analysis P-values=5.5 × 10-07, 5.4 × 10-07 and 1.0 × 10-07). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10-316) and the central nervous system (P-value=7.5 × 10- 321). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitte

Intravenous pamidronate in combination with calcium and vitamin D: highly effective in the treatment of low bone mineral density in inflammatory bowel disease

OBJECTIVE: Decreased bone mineral density (BMD) is common in inflammatory bowel disease (IBD) and an increased risk of fractures has been reported. Guidelines state bisphosphonate treatment for IBD patients with decreased BMD, but orally available bisphosphonates have been associated with gastrointestinal side effects and the absorption is poor. We investigated whether intravenous pamidronate is a safe and effective treatment. MATERIAL AND METHODS: Forty-nine IBD patients with decreased BMD as assessed by DEXA scan were treated with calcium 1000 mg and vitamin D 400 IU daily. In addition, 30 mg of pamidronate was administered intravenously every 3 months. DEXA scanning was performed prior to treatment, after 6 months and after 1 year. RESULTS: Of 49 IBD patients, 40 were osteoporotic and 9 were osteopenic. Twenty-six patients were female (mean age 40.8) and 23 were male (mean age 43.3). Treatment was discontinued in one patient because of fever after infusion. Otherwise, tolerability was excellent, and no adverse events were documented. A mean 0.51 increase of lumbar spine (L1-L4) T-scores was observed (CI 95% 0.35-0.67; p <0.0004). The effect of treatment on left femoral neck T-scores was less pronounced: 0.39 (CI 95% 0.24-0.53; p <0.0004). CONCLUSIONS: We conclude that intravenous pamidronate in combination with calcium and vitamin D is a well tolerated strategy for treating Crohn's disease associated osteopenia and osteoporosis. Although uncontrolled, treatment results in a significant increase of BMD in the lumbar spin

Infliximab treatment for Crohn's disease: One-year experience in a Dutch academic hospital

The aim of this study was to report the 1-year clinical experience with infliximab treatment for Crohn's disease (CD) in the Netherlands. All 73 CD patients receiving infliximab infusions were prospectively followed during I year after the drugs' registration in the Netherlands. Clinical response and adverse events were assessed for both active luminal disease as well as fistulous disease. A total of 2121 infusions were administered to 57 patients with active luminal CD and 16 patients with fistulous CD. The mean duration between infusions was 60 days. In 17% of patients, adverse events were recorded, of which one was serious. The response rate was 81% in active luminal CD and 87% in fistulous disease. Response rates were highest in patients receiving concomitant methotrexate as maintenance therapy. Steroids could successfully be tapered off in 73% of responding luminal CD patients and 100% of responding CD patients with fistulae. Eleven patients showed a loss of response to continuous infliximab readministration. Our clinical experience with infliximab for active luminal and fistulous CD showed that the administration is safe, effective, and has high steroid-sparing efficacy. Higher response rates were seen with methotrexate as concomitant medicatio

A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis

GOALS: To evaluate the safety and efficacy of infliximab in patients with primary sclerosing cholangitis. STUDY: In this double-blind, placebo-controlled study, 24 patients with primary sclerosing cholangitis were screened and randomly assigned in a 2:1 ratio to receive infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, 12, 18, and 24; patients were followed through week 52. The primary efficacy end point was a decrease of at least 50% in the serum alkaline phosphatase level from baseline to week 18. A blinded histologic assessment of liver biopsy samples, obtained at weeks 0 and 26, was performed using a predefined scoring system, including scores for inflammation, fibrosis, and cholestasis. RESULTS: Patient enrollment was prematurely stopped when results of an interim analysis showed no significant treatment benefit. Of the 24 patients screened, 10 were enrolled (6 patients received infliximab). Mean alkaline phosphatase levels at weeks 0, 18, and 52 were 349, 330, and 389 U/L, respectively, for the infliximab group and 481, 438, and 391 U/L, respectively, for the placebo group. Liver biopsy samples were analyzed in 7 patients (4 infliximab); no apparent differences could be detected in any of the histologic parameters. In 3 of 4 infliximab-treated patients and 2 of 3 placebo-treated patients, the disease stage did not change after 6 months of treatment. No meaningful changes were detected in the symptom score. No serious drug-related adverse events were observed. CONCLUSIONS: Study findings failed to demonstrate efficacy of infliximab in this small group of patients with established primary sclerosing cholangiti

Thyroid State Regulates Gene Expression in Human Whole Blood

Context: Despite the well-recognized clinical features resulting from insufficient or excessive thyroid hormone (TH) levels in humans, it is largely unknown which genes are regulated by TH in human tissues.Objective: To study the effect of TH on human gene expression profiles in whole blood, mainly consisting of T3 receptor (TR) alpha-expressing cells.Methods: We performed next-generation RNA sequencing on whole blood samples from eight athyroid patients (four females) on and after 4 weeks off levothyroxine replacement. Gene expression changes were analyzed through paired differential expression analysis and confirmed in a validation cohort. Weighted gene coexpression network analysis (WGCNA) was applied to identify thyroid state-related networks.Results: We detected 486 differentially expressed genes (fold-change &gt;1.5; multiple testing corrected P value &lt; 0.05), of which 76% were positively and 24% were negatively regulated. Gene ontology (GO) enrichment analysis revealed that three biological processes were significantly overrepresented, of which the process translational elongation showed the highest fold enrichment (7.3-fold, P = 1.8 x 10(-6)). WGCNA analysis independently identified various gene clusters that correlated with thyroid state. Further GO analysis suggested that thyroid state affects platelet function.Conclusions: Changes in thyroid state regulate numerous genes in human whole blood, predominantly TR alpha-expressing leukocytes. In addition, TH may regulate gene transcripts in platelets

Exome-Wide Meta-Analysis Identifies Rare 3′-UTR Variant in ERCC1/CD3EAP Associated with Symptoms of Sleep Apnea

Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10−9, βmeta = 0.99). Rs2229918 overlaps with the 3′ untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research

Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation

Faecal microbiota transplantation (FMT) may contribute towards disease remission in ulcerative colitis (UC), but it is unknown which factors determine long-term effect of treatment. Here, we aimed to identify bacterial signatures associated with sustained remission. To this end, samples from healthy donors and UC patients—grouped into responders and non-responders at a primary end point (week 12) and further stratified by sustained clinical remission and relapse assessed at ⩾1-year follow-up were analysed, comparing the efficacy of FMT from either a healthy donor or autologous faeces. Microbiota composition was determined with a 16S rRNA gene-based phylogenetic microarray on faecal and mucosal samples, and functional profiles were predicted using PICRUSt with quantitative PCR verification of the butyrate production capacity; short-chain fatty acids were measured in faecal samples. At baseline, UC patients showed reduced amounts of bacterial groups from the Clostridium cluster XIVa, and significantly higher levels of Bacteroidetes as compared with donors. These differences were reduced after FMT mostly in responders. Sustained remission was associated with known butyrate producers and overall increased butyrate production capacity, while relapse was associated with Proteobacteria and Bacteroidetes. Ruminococcus gnavus was found at high levels in donors of failed FMT. A microbial ecosystem rich in Bacteroidetes and Proteobacteria and low in Clostridium clusters IV and XIVa observed in UC patients after FMT was predictive of poor sustained response, unless modified with a donor microbiota rich in specific members from the Clostridium clusters IV and XIVa. Additionally, sustained response was associated with restoration of the butyrate production capacity.The ISME Journal advance online publication, 11 April 2017; doi:10.1038/ismej.2017.44.</p