Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts

OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11\u2005326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 710(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6

Ibrutinib may inhibitintestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion

Regulation of the Transglutaminase I gene

The transglutaminase I (TGase I) gene encodes an enzyme that catalyzes the cross-linking of structural proteins involved in the formation of the cornified envelope during squamous cell differentiation. To identify DNA elements important for the transcriptional control of the TGase I gene, we analyzed the ability of a 2.9-kilobase pair (kb) upstream regulatory region to control the expression of a reporter gene in vivo and in vitro. Transgenic mice bearing the pTG(-2.9kb)CAT construct exhibited the same pattern of tissue-specific expression of CAT as reported for TGase I. Deletion analysis in transiently transfected rabbit tracheal epithelial cells indicated that two sequences from bp -490 to -470 and from -54 to -37 are involved in the activation of TGase I transcription. Point mutation analysis and mobility shift assays showed that the sequence located between -54 and -37 is a functional Sp1-like transcription element. Sp1 and Sp3, but not Sp2, are part of nuclear protein complexes from differentiated RbTE cells binding to this site. The element TGATGTCA between bp -490 and -470 is contained in a larger 22-bp palindrome and resembles the consensus cAMP response element-binding protein (CREB)/AP-1 element recognized by dimeric complexes of members of the CREB, ATF, Fos, and Jun families. Mutations in this sequence greatly reduced promoter activity. Supershift analysis identified CREB1, JunB, c-Fos, Fra-1, and c-Jun in protein complexes isolated from differentiated rabbit tracheal epithelial cells binding to this site. Our study shows that the Sp1- and CREB/AP-1-like sites act in concert to stimulate transcription of the TGase I gene. The 2.9-kb promoter region could guide expression of specific genes in the granular layer of the epidermis and could be useful in gene therapy

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Der seltene Nierentumor

Renewable energy is one of the most important and widely researched topics today. It is classically defined as any form of energy coming from any naturally replenish-able source. This may include everything from solar to wind power, as well as biomass or biofuels. When considering biomass, or any (living or recently-dead) biological material, the chemical energy of the molecules is generally collected through combustion. The area of liquid fuels from biomass has especially gained much notoriety and support in recent years. This is due to the lower emissions and clean-burning nature of these fuels when compared to more traditional approaches, as well as the obvious renewable nature of the starting material. While vegetable oils or animal fats can be used as a replacement for diesel fuels, corn, switchgrass, or other grains are more widely used to produce ethanol for use in common combustion engines. Today’s E85 fuel is sold to customers with a chemical makeup of 85% ethanol and 15% gasoline. The use of solid biomass as a direct supplier of energy, however, is an area still left relatively unexplored in this growing field. In theory, and as preliminary research suggests, harvesting energy directly from solid biomass may be considerably more efficient than gathering it from its processed liquid counterpart. In fact, some studies suggest that the energy acquired from burning ethanol is up to 67% lower than is contained in the plant cellulose from which it is derived.[1] There are, however, several other factors besides energy projections to consider when looking at the economic and market viability of such an approach. For example, one of the main advantages of liquid fuels over solid is the ease of transportation and storage. Additionally, the feasibility of developing a whole new process of biomass collection and processing must be balanced with economic and logistical constraints. This includes not only careful analysis of energy and cost balances, but also in-depth examination of all equipment, manpower and environmental limitations. IPRO 349 was established to examine these (and many more) considerations in the viability of sold fuel from biomass. Specifically, we have narrowed the scope of our research to biomass derived from corn stover (leaves and stalk left in the ground after harvesting) within the state of Illinois. Illinois was chosen because it is currently the largest producer of corn in the nation.[2] Corn stover has been shown to have an energy content of 5,290 Btu/lb. wet, and 7,560 Btu/lb. dry.[2]With such an approach, it may be possible to utilize what would otherwise be considered “waste” to produce useable, renewable energy. For the purposes of this project, cogeneration, or the simultaneous generation of both electricity and useful heat will be examined.Deliverable

Solid Fuel from Biomass for Cogeneration (Semester Unknown) IPRO 349: Solid Fuel from Biomass for Cogeneration IPRO 349 Project Plan Sp08

Renewable energy is one of the most important and widely researched topics today. It is classically defined as any form of energy coming from any naturally replenish-able source. This may include everything from solar to wind power, as well as biomass or biofuels. When considering biomass, or any (living or recently-dead) biological material, the chemical energy of the molecules is generally collected through combustion. The area of liquid fuels from biomass has especially gained much notoriety and support in recent years. This is due to the lower emissions and clean-burning nature of these fuels when compared to more traditional approaches, as well as the obvious renewable nature of the starting material. While vegetable oils or animal fats can be used as a replacement for diesel fuels, corn, switchgrass, or other grains are more widely used to produce ethanol for use in common combustion engines. Today’s E85 fuel is sold to customers with a chemical makeup of 85% ethanol and 15% gasoline. The use of solid biomass as a direct supplier of energy, however, is an area still left relatively unexplored in this growing field. In theory, and as preliminary research suggests, harvesting energy directly from solid biomass may be considerably more efficient than gathering it from its processed liquid counterpart. In fact, some studies suggest that the energy acquired from burning ethanol is up to 67% lower than is contained in the plant cellulose from which it is derived.[1] There are, however, several other factors besides energy projections to consider when looking at the economic and market viability of such an approach. For example, one of the main advantages of liquid fuels over solid is the ease of transportation and storage. Additionally, the feasibility of developing a whole new process of biomass collection and processing must be balanced with economic and logistical constraints. This includes not only careful analysis of energy and cost balances, but also in-depth examination of all equipment, manpower and environmental limitations. IPRO 349 was established to examine these (and many more) considerations in the viability of sold fuel from biomass. Specifically, we have narrowed the scope of our research to biomass derived from corn stover (leaves and stalk left in the ground after harvesting) within the state of Illinois. Illinois was chosen because it is currently the largest producer of corn in the nation.[2] Corn stover has been shown to have an energy content of 5,290 Btu/lb. wet, and 7,560 Btu/lb. dry.[2]With such an approach, it may be possible to utilize what would otherwise be considered “waste” to produce useable, renewable energy. For the purposes of this project, cogeneration, or the simultaneous generation of both electricity and useful heat will be examined.Deliverable

Solid Fuel from Biomass for Cogeneration (Semester Unknown) IPRO 349: Solid Fuel from Biomass for Cogeneration IPRO 349 Poster2 Sp08

Renewable energy is one of the most important and widely researched topics today. It is classically defined as any form of energy coming from any naturally replenish-able source. This may include everything from solar to wind power, as well as biomass or biofuels. When considering biomass, or any (living or recently-dead) biological material, the chemical energy of the molecules is generally collected through combustion. The area of liquid fuels from biomass has especially gained much notoriety and support in recent years. This is due to the lower emissions and clean-burning nature of these fuels when compared to more traditional approaches, as well as the obvious renewable nature of the starting material. While vegetable oils or animal fats can be used as a replacement for diesel fuels, corn, switchgrass, or other grains are more widely used to produce ethanol for use in common combustion engines. Today’s E85 fuel is sold to customers with a chemical makeup of 85% ethanol and 15% gasoline. The use of solid biomass as a direct supplier of energy, however, is an area still left relatively unexplored in this growing field. In theory, and as preliminary research suggests, harvesting energy directly from solid biomass may be considerably more efficient than gathering it from its processed liquid counterpart. In fact, some studies suggest that the energy acquired from burning ethanol is up to 67% lower than is contained in the plant cellulose from which it is derived.[1] There are, however, several other factors besides energy projections to consider when looking at the economic and market viability of such an approach. For example, one of the main advantages of liquid fuels over solid is the ease of transportation and storage. Additionally, the feasibility of developing a whole new process of biomass collection and processing must be balanced with economic and logistical constraints. This includes not only careful analysis of energy and cost balances, but also in-depth examination of all equipment, manpower and environmental limitations. IPRO 349 was established to examine these (and many more) considerations in the viability of sold fuel from biomass. Specifically, we have narrowed the scope of our research to biomass derived from corn stover (leaves and stalk left in the ground after harvesting) within the state of Illinois. Illinois was chosen because it is currently the largest producer of corn in the nation.[2] Corn stover has been shown to have an energy content of 5,290 Btu/lb. wet, and 7,560 Btu/lb. dry.[2]With such an approach, it may be possible to utilize what would otherwise be considered “waste” to produce useable, renewable energy. For the purposes of this project, cogeneration, or the simultaneous generation of both electricity and useful heat will be examined.Deliverable

Solid Fuel from Biomass for Cogeneration (Semester Unknown) IPRO 349: Solid Fuel from Biomass for Cogeneration IPRO 349 Ethics Sp08

Renewable energy is one of the most important and widely researched topics today. It is classically defined as any form of energy coming from any naturally replenish-able source. This may include everything from solar to wind power, as well as biomass or biofuels. When considering biomass, or any (living or recently-dead) biological material, the chemical energy of the molecules is generally collected through combustion. The area of liquid fuels from biomass has especially gained much notoriety and support in recent years. This is due to the lower emissions and clean-burning nature of these fuels when compared to more traditional approaches, as well as the obvious renewable nature of the starting material. While vegetable oils or animal fats can be used as a replacement for diesel fuels, corn, switchgrass, or other grains are more widely used to produce ethanol for use in common combustion engines. Today’s E85 fuel is sold to customers with a chemical makeup of 85% ethanol and 15% gasoline. The use of solid biomass as a direct supplier of energy, however, is an area still left relatively unexplored in this growing field. In theory, and as preliminary research suggests, harvesting energy directly from solid biomass may be considerably more efficient than gathering it from its processed liquid counterpart. In fact, some studies suggest that the energy acquired from burning ethanol is up to 67% lower than is contained in the plant cellulose from which it is derived.[1] There are, however, several other factors besides energy projections to consider when looking at the economic and market viability of such an approach. For example, one of the main advantages of liquid fuels over solid is the ease of transportation and storage. Additionally, the feasibility of developing a whole new process of biomass collection and processing must be balanced with economic and logistical constraints. This includes not only careful analysis of energy and cost balances, but also in-depth examination of all equipment, manpower and environmental limitations. IPRO 349 was established to examine these (and many more) considerations in the viability of sold fuel from biomass. Specifically, we have narrowed the scope of our research to biomass derived from corn stover (leaves and stalk left in the ground after harvesting) within the state of Illinois. Illinois was chosen because it is currently the largest producer of corn in the nation.[2] Corn stover has been shown to have an energy content of 5,290 Btu/lb. wet, and 7,560 Btu/lb. dry.[2]With such an approach, it may be possible to utilize what would otherwise be considered “waste” to produce useable, renewable energy. For the purposes of this project, cogeneration, or the simultaneous generation of both electricity and useful heat will be examined.Deliverable

Solid Fuel from Biomass for Cogeneration (Semester Unknown) IPRO 349

Renewable energy is one of the most important and widely researched topics today. It is classically defined as any form of energy coming from any naturally replenish-able source. This may include everything from solar to wind power, as well as biomass or biofuels. When considering biomass, or any (living or recently-dead) biological material, the chemical energy of the molecules is generally collected through combustion. The area of liquid fuels from biomass has especially gained much notoriety and support in recent years. This is due to the lower emissions and clean-burning nature of these fuels when compared to more traditional approaches, as well as the obvious renewable nature of the starting material. While vegetable oils or animal fats can be used as a replacement for diesel fuels, corn, switchgrass, or other grains are more widely used to produce ethanol for use in common combustion engines. Today’s E85 fuel is sold to customers with a chemical makeup of 85% ethanol and 15% gasoline. The use of solid biomass as a direct supplier of energy, however, is an area still left relatively unexplored in this growing field. In theory, and as preliminary research suggests, harvesting energy directly from solid biomass may be considerably more efficient than gathering it from its processed liquid counterpart. In fact, some studies suggest that the energy acquired from burning ethanol is up to 67% lower than is contained in the plant cellulose from which it is derived.[1] There are, however, several other factors besides energy projections to consider when looking at the economic and market viability of such an approach. For example, one of the main advantages of liquid fuels over solid is the ease of transportation and storage. Additionally, the feasibility of developing a whole new process of biomass collection and processing must be balanced with economic and logistical constraints. This includes not only careful analysis of energy and cost balances, but also in-depth examination of all equipment, manpower and environmental limitations. IPRO 349 was established to examine these (and many more) considerations in the viability of sold fuel from biomass. Specifically, we have narrowed the scope of our research to biomass derived from corn stover (leaves and stalk left in the ground after harvesting) within the state of Illinois. Illinois was chosen because it is currently the largest producer of corn in the nation.[2] Corn stover has been shown to have an energy content of 5,290 Btu/lb. wet, and 7,560 Btu/lb. dry.[2]With such an approach, it may be possible to utilize what would otherwise be considered “waste” to produce useable, renewable energy. For the purposes of this project, cogeneration, or the simultaneous generation of both electricity and useful heat will be examined.Deliverable

Solid Fuel from Biomass for Cogeneration (Semester Unknown) IPRO 349: Solid Fuel from Biomass for Cogeneration IPRO 349 Brochure Sp08

Renewable energy is one of the most important and widely researched topics today. It is classically defined as any form of energy coming from any naturally replenish-able source. This may include everything from solar to wind power, as well as biomass or biofuels. When considering biomass, or any (living or recently-dead) biological material, the chemical energy of the molecules is generally collected through combustion. The area of liquid fuels from biomass has especially gained much notoriety and support in recent years. This is due to the lower emissions and clean-burning nature of these fuels when compared to more traditional approaches, as well as the obvious renewable nature of the starting material. While vegetable oils or animal fats can be used as a replacement for diesel fuels, corn, switchgrass, or other grains are more widely used to produce ethanol for use in common combustion engines. Today’s E85 fuel is sold to customers with a chemical makeup of 85% ethanol and 15% gasoline. The use of solid biomass as a direct supplier of energy, however, is an area still left relatively unexplored in this growing field. In theory, and as preliminary research suggests, harvesting energy directly from solid biomass may be considerably more efficient than gathering it from its processed liquid counterpart. In fact, some studies suggest that the energy acquired from burning ethanol is up to 67% lower than is contained in the plant cellulose from which it is derived.[1] There are, however, several other factors besides energy projections to consider when looking at the economic and market viability of such an approach. For example, one of the main advantages of liquid fuels over solid is the ease of transportation and storage. Additionally, the feasibility of developing a whole new process of biomass collection and processing must be balanced with economic and logistical constraints. This includes not only careful analysis of energy and cost balances, but also in-depth examination of all equipment, manpower and environmental limitations. IPRO 349 was established to examine these (and many more) considerations in the viability of sold fuel from biomass. Specifically, we have narrowed the scope of our research to biomass derived from corn stover (leaves and stalk left in the ground after harvesting) within the state of Illinois. Illinois was chosen because it is currently the largest producer of corn in the nation.[2] Corn stover has been shown to have an energy content of 5,290 Btu/lb. wet, and 7,560 Btu/lb. dry.[2]With such an approach, it may be possible to utilize what would otherwise be considered “waste” to produce useable, renewable energy. For the purposes of this project, cogeneration, or the simultaneous generation of both electricity and useful heat will be examined.Deliverable