DOCSLIB.ORG

Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 Loci Associate

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 Loci Associate Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com Gut Online First, published on September 25, 2014 as 10.1136/gutjnl-2014-307453 Pancreas ORIGINAL ARTICLE Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study Monique H Derikx,1,* Peter Kovacs,2,* Markus Scholz,3,4,* Emmanuelle Masson,5,6,7,8 Jian-Min Chen,5,6,7,8 Claudia Ruffert,9,* Peter Lichtner,10,* Rene H M te Morsche,1,* Giulia Martina Cavestro,11,* PanEuropean Working group on Alcoholic Chronic Pancreatitis members and collaborators,† Claude Férec,5,6,7,8 Joost P H Drenth,1,* Heiko Witt,12,* Jonas Rosendahl9,* ▸ Additional material is ABSTRACT published online only. To view Objective Several genetic risk factors have been Significance of this study please visit the journal online fi (http://dx.doi.org/10.1136/ identi ed for non-alcoholic chronic pancreatitis (NACP). gutjnl-2014-307453). A genome-wide association study reported an fi association of chronic pancreatitis (CP) with variants in What is already known on this subject? For numbered af liations see – end of article. PRSS1 PRSS2 (rs10273639; near the gene encoding ▸ Genetic associations for non-alcoholic chronic cationic trypsinogen) and CLDN2–MORC4 loci pancreatitis (NACP) in PRSS1, PRSS2, CFTR, Correspondence to (rs7057398 in RIPPLY1 and rs12688220 in MORC4). SPINK1, CTRC and CPA1, as well as a Dr Jonas Rosendahl, We aimed to refine these findings in a large European gene-dosage effect of PRSS1-PRSS2 locus have Department of Internal fi Medicine, Neurology and cohort. been identi ed. Dermatology, Division of Design We studied 3062 patients with alcohol-related ▸ Alcohol misuse is the predominant cause of Gastroenterology and CP (ACP) or NACP and 5107 controls. Also, 1559 chronic pancreatitis (CP); however, only Rheumatology, University Clinic German patients with alcohol-associated cirrhosis or 3%–5% of alcohol misusers develop the of Leipzig, Liebigstraße 20, alcohol dependence were included for comparison. We disease. This implicates genetic susceptibility Leipzig 04103, Germany; – [email protected] performed several meta-analyses to examine genotype factors, which have not been elucidated so far. leipzig.de phenotype relationships. ▸ A recent genome-wide association study Results Association with ACP was found for (GWAS) reported PRSS1–PRSS2 and CLDN2– *Members of the PanEuropean rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was MORC4 Working group on Alcoholic locus variants that affect risk for CP, Chronic Pancreatitis. also associated with variants rs7057398 and and the data have not been replicated up to rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 now. †Names and affiliations of the and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in rest of the co-authors are listed women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; What are the new findings? at the end of the manuscript. 95% CI 1.41 to 2.07, respectively). Similar results were ▸ This study in a large European cohort replicates obtained when German patients with ACP were and refines the impact of PRSS1-PRSS2 and MHD, PK, MS, EM, CF, JPHD CLDN2 MORC4 and HW contributed equally. compared with those with alcohol-associated cirrhosis or - locus variants as susceptibility alcohol dependence. In the overall population of patients factors predominantly in ACP. Received 11 April 2014 with NACP, association with rs10273639 was absent ▸ Variants at both loci are susceptibility factors Revised 18 August 2014 for ACP and not alcohol misuse per se Accepted 21 August 2014 (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms according to our comparison with alcohol- was associated with NACP in women only (OR, 1.32; dependent and patients with alcoholic liver 95% CI 1.15 to 1.51). cirrhosis. Conclusions The single-nucleotide polymorphisms ▸ Risk increase for the X chromosomal rs10273639 at the PRSS1–PRSS2 locus and rs7057398 CLDN2-MORC4 locus is comparable in men and and rs12688220 at the CLDN2–MORC4 locus are women. As such this factor does not explain associated with CP and strongly associate with ACP, but any sex differences in disease susceptibility. only rs7057398 with NACP in female patients. How might it impact on clinical practice in the foreseeable future? ▸ The replication and refinement of the recently identified susceptibility variants justifies further INTRODUCTION studies on their functional properties. To cite: Derikx MH, The genetic susceptibility to chronic pancreatitis (CP) Kovacs P, Scholz M, et al. ▸ By the identification of new pathways, new Gut Published Online First: is best illustrated by the discovery of cationic tryp- strategies for influencing the clinical picture of PRSS1 [please include Day Month sinogen mutations ( HGNC:9475) in families NACP and ACP might be developed in the long 1 Year] doi:10.1136/gutjnl- with autosomal-dominant inherited pancreatitis. term. 2014-307453 There is also strong evidence that genetic variants Copyright Article author (or their employer)Derikx MH, et al2014.. Gut 2014; Produced0:1–8. doi:10.1136/gutjnl-2014-307453 by BMJ Publishing Group Ltd (& BSG) under licence.1 Downloaded from gut.bmj.com on September 30, 2014 - Published by group.bmj.com Pancreas contribute to cases of CP without a clear inheritance pattern. We labelled patients with NACP in the absence of exogenous Indeed, idiopathic CP (ICP) is associated with genetic alterations factors such as alcohol. in CFTR (HGNC:1884), SPINK1 (HGNC:11244), PRSS2 ALC was diagnosed by a history of habitual ethanol intake (HGNC:9483), CTRC (HGNC:2523) and CPA1 (see ACP diagnosis above, duration at least 10 years), typical – (HGNC:2296).2 7 The association of genetic variants and disease findings in liver biopsy or clinical and laboratory findings indica- susceptibility is less clear for alcohol-related CP (ACP). There is a tive for liver disease. Such laboratory and clinical findings low enrichment of SPINK1 (p.N34S) and CTRC (p.R254W) included abnormal levels of aminotransferases, gamma glutamyl alleles in ACP populations, and no other consistent genetic risk transpeptidase, coagulation tests, serum albumin concentration, contributors have been described.58Similar to ICP,thePRSS2 platelet count, complications related to liver cirrhosis such as p.G191R variant protects against ACP development.2 All these oesophageal varices, ascites, hepatic encephalopathy and typical associations have been discovered through candidate-driven liver morphology in imaging studies. Other aetiologies of liver genetic association studies. cirrhosis were excluded by standard laboratory tests. A recent paper described a different approach and reported Patients with AD were recruited from psychiatric and addiction novel risk and protecting loci for CP identified through a medicine departments in different cities across southern and genome-wide association study (GWAS). A number of variants central Germany. AD was diagnosed per DSM-IV criteria by con- in the PRSS1–PRSS2 but also the CLDN2–MORC4 locus sensus of two clinical psychiatrists. All patients were of self- (Claudin 2; HGNC:2041; RIPPLY1, ripply transcriptional reported German ancestry and did not suffer from CP or ALC.16 repressor 1, HGNC:25117; MORC4, MORC family CW-type The study included 1866 patients (male, n=1567) with ACP zinc finger 4, HGNC:23485) were captured as risk factors for and 1196 patients (male, n=596) with NACP from different CP.9 This study investigated patients with different types of CP European countries. In addition, we enrolled 5107 controls as well as recurrent acute pancreatitis (RAP) and stratified indivi- (male, n=2287), 661 German patients with ALC (male, n=480) duals into alcohol-related and alcohol-unrelated pancreatitis and 898 Germans with AD (male, n=797). Characteristics of the groups. In a first screening cohort, three single nucleotide poly- patients and controls are summarised in table 1. More details of morphisms (SNPs) rs10273639 (in the PRSS1–PRSS2 locus on the controls are summarised in online supplementary table S1. chromosome 7, in perfect linkage disequilibrium with rs2011216 in intron 1 and rs6667 in exon 5 of PRSS1), Genotyping rs7057398 and rs12688220 (both in a new locus, CLDN2– Details of the methods used for genotyping are summarised in MORC4 on the X chromosome) reached genome-wide signifi- the online supplementary material. As quality controls, 3% of cance. After scrutiny, the PRSS1–PRSS2 rs10273639 T allele all samples were genotyped in duplicates blinded to the investi- appeared to protect against CP, whereas RIPPLY1 rs7057398 C gator. The concordance rate was >98%. Call rates for allele and MORC4 rs12688220 T allele increased disease suscep- rs10273639, rs7057398 and rs12688220 in the European tibility.9 There is some biological plausibility for the association samples were 99.1% (9641/9730), 99% (9636/9730) and with the PRSS1–PRSS2 locus as it may disturb the balance of 98.8% (9609/9730), respectively. pancreatic proteases and antiproteases in favour of the former.10 11 Claudin 2 represents a tight junction protein Statistical analysis involved in low-resistance cation-selective ion and water trans- Quality of SNP genotypes was assessed by study-wise call rate port between endothelial cells.12 13 One might speculate that and exact test for Hardy–Weinberg equilibrium in controls CLDN2–MORC4 locus variants lead to miss-localisation of pan- (female controls only for the X chromosomal SNPs). We also creatic CLDN2 that hampers its biological function. However, calculated overall statistics and performed stratified tests of this speculation warrants further experimental support. Hardy–Weinberg equilibrium according to Troendle and Yu.17 Prior to the design of experimental studies that focus on the According to these measures, genotype qualities were excellent biological role of these variants, it is crucial that GWAS results throughout. Study-wise genetic effects were determined by are replicated.
Load more

Recommended publications
  • PARSANA-DISSERTATION-2020.Pdf
    DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks.
    [Show full text]
  • Identification of Pancreatic Juice Proteins As Biomarkers of Pancreatic Cancer
    1683-1692.qxd 23/4/2010 10:57 Ì ™ÂÏ›‰·1683 ONCOLOGY REPORTS 23: 1683-1692, 2010 Identification of pancreatic juice proteins as biomarkers of pancreatic cancer JUN GAO1*, FENG ZHU1*, SHUNLI LV1*, ZHAOSHEN LI1, ZHANG LING1, YANFANG GONG1, CHEN JIE1 and LIE MA2 1Department of Gastroenterology, Changhai Hospital, 2Department of Biochemistry, Basic Medicine, Second Military Medical University, Shanghai 200433, P.R. China Received December 17, 2009; Accepted February 4, 2010 DOI: 10.3892/or_00000812 Abstract. Pancreatic juice is a potential source of proteins analysis of pancreatic juice from PC patients is a powerful associated with pancreatic cancer (PC) due to the proximity of method to find new PC biomarkers. Hyperexpression of the ducts to tumor tissue. Therefore, screening of proteins in PRSS2 gene and hypermethylation of ELA3B gene promoter pancreatic juice from PC patients may identify new PC were associated with PC, raising the possibility of their biomarkers. We analyzed pancreatic juice from patients with application as new biomarkers in PC diagnosis and screening. pancreatic diseases including PC, chronic pancreatitis (CP) and simple choledocholithiasis (CDS) by 2-DE. Protein spots Introduction from PC patients that changed >2-fold compared with both CP and CDS were selected and identified by mass spectro- Pancreatic cancer (PC) is an almost uniformly fatal disease, metry (MS). mRNA levels were measured by QRT-PCR in with a 5-year survival rate of less than 4%. In the United PC cell lines, PC tissues and adjacent pancreatic normal (PN) States, PC is the 4th leading cause of cancer death, while in tissues. Relationships between mRNA levels in PC tissues Europe it is the 6th (1).
    [Show full text]
  • B Inhibition in a Mouse Model of Chronic Colitis1
    The Journal of Immunology Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-␬B Inhibition in a Mouse Model of Chronic Colitis1 Feng Wu and Shukti Chakravarti2 Fibrosis is a major complication of chronic inflammation, as seen in Crohn’s disease and ulcerative colitis, two forms of inflam- matory bowel diseases. To elucidate inflammatory signals that regulate fibrosis, we investigated gene expression changes under- lying chronic inflammation and fibrosis in trinitrobenzene sulfonic acid-induced murine colitis. Six weekly 2,4,6-trinitrobenzene sulfonic acid enemas were given to establish colitis and temporal gene expression patterns were obtained at 6-, 8-, 10-, and 12-wk time points. The 6-wk point, TNBS-w6, was the active, chronic inflammatory stage of the model marked by macrophage, neu- trophil, and CD3؉ and CD4؉ T cell infiltrates in the colon, consistent with the idea that this model is T cell immune response driven. Proinflammatory genes Cxcl1, Ccl2, Il1b, Lcn2, Pla2g2a, Saa3, S100a9, Nos2, Reg2, and Reg3g, and profibrogenic extra- cellular matrix genes Col1a1, Col1a2, Col3a1, and Lum (lumican), encoding a collagen-associated proteoglycan, were up-regulated at the active/chronic inflammatory stages. Rectal administration of the NF-␬B p65 antisense oligonucleotide reduced but did not abrogate inflammation and fibrosis completely. The antisense oligonucleotide treatment reduced total NF-␬B by 60% and down- regulated most proinflammatory genes. However, Ccl2, a proinflammatory chemokine known to promote fibrosis, was not down- regulated. Among extracellular matrix gene expressions Lum was suppressed while Col1a1 and Col3a1 were not. Thus, effective treatment of fibrosis in inflammatory bowel disease may require early and complete blockade of NF-␬B with particular attention to specific proinflammatory and profibrogenic genes that remain active at low levels of NF-␬B.
    [Show full text]
  • PRSS2 Polyclonal Antibody
    PRODUCT DATA SHEET Bioworld Technology,Inc. PRSS2 polyclonal antibody Catalog: BS61619 Host: Rabbit Reactivity: Human,Mouse,Rat BackGround: Applications: This gene belongs to the trypsin family of serine proteas- WB: 1:500~1:1000 es and encodes anionic trypsinogen. It is part of a cluster Storage&Stability: of trypsinogen genes that are located within the T cell re- Store at 4°C short term. Aliquot and store at -20°C long ceptor beta locus. Enzymes of this family cleave peptide term. Avoid freeze-thaw cycles. bonds that follow lysine or arginine residues. This protein Specificity: is found at high levels in pancreatic juice and its upregu- PRSS2 polyclonal antibody detects endogenous levels of lation is a characteristic feature of pancreatitis. This pro- PRSS2 protein. tein has also been found to activate pro-urokinase in DATA: ovarian tumors, suggesting a function in tumor invasion. In addition, this enzyme is able to cleave across the type II collagen triple helix in rheumatoid arthritis synovitis tissue, potentially participating in the degradation of type II collagen-rich cartilage matrix. Alternative splicing re- sults in multiple transcript variants. Product: Western blot (WB) analysis of PRSS2 polyclonal antibody at 1:500 Rabbit IgG, 1mg/ml in PBS with 0.02% sodium azide, dilution 50% glycerol, pH7.2 Lane1:HT102 whole cell lysate(40ug) Molecular Weight: Lane2:SW620 whole cell lysate(40ug) ~ 26 kDa Lane3:CT26 whole cell lysate(40ug) Swiss-Prot: Lane4:PC12 whole cell lysate(40ug) P07478 Note: Purification&Purity: For research use only, not for use in diagnostic procedure. The antibody was affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific im- munogen and the purity is > 95% (by SDS-PAGE).
    [Show full text]
  • Trypsin-Encoding PRSS1-PRSS2 Variations
    ARTICLE Acute Lymphoblastic Leukemia Ferrata Storti Foundation Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report Haematologica 2019 Benjamin O. Wolthers,1 Thomas L. Frandsen,1 Chirag J. Patel,2 Rachid Abaji,3 Volume 104(3):556-563 Andishe Attarbaschi,4 Shlomit Barzilai,5 Antonella Colombini,6 Gabriele Escherich,7 Marie Grosjean,8 Maja Krajinovic,3,9 Eric Larsen,10 Der-Cherng Liang,11 Anja Möricke,12 Kirsten K. Rasmussen,1 Sujith Samarasinghe,13 Lewis B. Silverman,14 Inge M. van der Sluis,15 Martin Stanulla,16 Morten Tulstrup,1 Rachita Yadav,8,17 Wenjian Yang,18 Ester Zapotocka,19 Ramneek Gupta8 and Kjeld Schmiegelow1,20 on behalf of the Ponte di Legno toxicity working group 1Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; 3CHU Sainte-Justine Research Center and Department of Pharmacology, University of Montreal, QC, Canada; 4Department of Pediatric Hematology and Oncology, St Anna Children's Hospital and Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Austria; 5Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Israel; 6Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy;
    [Show full text]
  • Irf2)Intrypsinogen5 Gene Transcription
    Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2)intrypsinogen5 gene transcription Hideki Hayashia, Tomoko Kohnoa, Kiyoshi Yasuia, Hiroyuki Murotab, Tohru Kimurac, Gordon S. Duncand, Tomoki Nakashimae, Kazuo Yamamotod, Ichiro Katayamab, Yuhua Maa, Koon Jiew Chuaa, Takashi Suematsua, Isao Shimokawaf, Shizuo Akirag, Yoshinao Kuboa, Tak Wah Makd,1, and Toshifumi Matsuyamaa,h,1 aDivision of Cytokine Signaling, Department of Molecular Biology and Immunology and fDepartment of Investigative Pathology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan; Departments of bDermatology and cPathology, Graduate School of Medicine and gDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; dCampbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9; eDepartment of Cell Signaling, Tokyo Medical and Dental University, Tokyo 113-8549, Japan; and hGlobal Center of Excellence Program, Nagasaki University, Nagasaki 852-8523, Japan Contributed by Tak Wah Mak, October 5, 2011 (sent for review September 8, 2011) − − Mice deficient for interferon regulatory factor (Irf)2 (Irf2 / mice) transcriptional activation of dsRNA-sensing PRRs were critical for exhibit immunological abnormalities and cannot survive lympho- the pIC-induced death. cytic choriomeningitis virus infection. The pancreas of these ani- mals is highly inflamed, a phenotype replicated by treatment with Results and Discussion − − poly(I:C), a synthetic double-stranded RNA. Trypsinogen5 mRNA Irf2 / Mice Show IFN-Dependent Poly(I:C)-Induced Pancreatitis and −/− IFN-Independent Secretory Dysfunction in Pancreatic Acinar Cells. was constitutively up-regulated about 1,000-fold in Irf2 mice − − LCMV-infected Irf2 / mice die within 4 wk postinfection (3), compared with controls as assessed by quantitative RT-PCR.
    [Show full text]
  • Mouse Trypsin 2 / PRSS2 Protein (His Tag)
    Mouse Trypsin 2 / PRSS2 Protein (His Tag) Catalog Number: 50383-M08H General Information SDS-PAGE: Gene Name Synonym: Prss2; Ta; Tesp4; Try2; TRY8; TRYP Protein Construction: A DNA sequence encoding the mouse PRSS2 (NP_033456.1) precursor (Met 1-Asn 246) was expressed, with a C-terminal polyhistidine tag. Source: Mouse Expression Host: HEK293 Cells QC Testing Purity: > 92 % as determined by SDS-PAGE Bio Activity： Protein Description Measured by its ability to cleave the fluorogenic peptide substrate, Mca- RPKPVE-Nval-WRK(Dnp)-NH2 (Anaspec, Catalog #27096) . The specific Trypsin-2, also known as Trypsin II, Anionic trypsinogen, Serine protease 2, activity is >1500 pmoles/min/μg . (Activation description: The proenzyme PRSS2 and TRY2, is a secreted protein which belongs to the trypsin serine needs to be activated by enteropeptidase for an activated form) protease family including Trypsin, PRSS1, PRSS2 and PRSS3. It consists of a signal peptide (residues 1-15), a pro region (residues 16-23), and a Endotoxin: proteolytically active mature chain (residues 24-247). PRSS2 contains onepeptidase S1 domain. It is secreted into theduodenum,hydrolysing < 1.0 EU per μg of the protein as determined by the LAL method peptides into their smaller building blocks, which is necessary for the uptake of protein in the food. It is secreted by the pancreas in the form of Stability: inactivezymogen,trypsinogen and cleaved to its active form in the small Samples are stable for up to twelve months from date of receipt at -70 ℃ intestine when the pancreas is stimulated bycholecystokinin through the common activation mechanism. Predicted N terminal: Phe 16 References Molecular Mass: 1.Rawlings, N.D.
    [Show full text]
  • Trypsin-Encoding PRSS1-PRSS2 Variations Influence the Risk Of
    Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase- associated pancreatitis in children with acute lymphoblastic leukemia A ponte di legno toxicity working group report on behalf of the Ponte di Legno toxicity working group Published in: Haematologica DOI: 10.3324/haematol.2018.199356 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Document license: CC BY-NC Citation for published version (APA): on behalf of the Ponte di Legno toxicity working group (2019). Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: A ponte di legno toxicity working group report. Haematologica, 104(3), 556-563. https://doi.org/10.3324/haematol.2018.199356 Download date: 30. Sep. 2021 ARTICLE Acute Lymphoblastic Leukemia Ferrata Storti Foundation Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report Haematologica 2019 Benjamin O. Wolthers,1 Thomas L. Frandsen,1 Chirag J. Patel,2 Rachid Abaji,3 Volume 104(3):556-563 Andishe Attarbaschi,4 Shlomit Barzilai,5 Antonella Colombini,6 Gabriele Escherich,7 Marie Grosjean,8 Maja Krajinovic,3,9 Eric Larsen,10 Der-Cherng Liang,11 Anja Möricke,12 Kirsten K. Rasmussen,1 Sujith Samarasinghe,13 Lewis B. Silverman,14 Inge M. van der Sluis,15 Martin Stanulla,16 Morten Tulstrup,1 Rachita Yadav,8,17 Wenjian Yang,18 Ester Zapotocka,19 Ramneek
    [Show full text]
  • Cervix Cancer
    Microarrays 2015, 4, 287-310; doi:10.3390/microarrays4020287 OPEN ACCESS microarrays ISSN 2076-3905 www.mdpi.com/journal/microarrays Article An Optimization-Driven Analysis Pipeline to Uncover Biomarkers and Signaling Paths: Cervix Cancer Enery Lorenzo 1, Katia Camacho-Caceres 1, Alexander J. Ropelewski 2, Juan Rosas 1, Michael Ortiz-Mojer 1, Lynn Perez-Marty 1, Juan Irizarry 1, Valerie Gonzalez 1, Jesús A. Rodríguez 1, Mauricio Cabrera-Rios 1 and Clara Isaza 1,3,* 1 Bio IE Lab, The Applied Optimization Group at UPRM, Industrial Engineering Department, University of Puerto Rico at Mayaguez, Call Box 9000, Mayagüez, PR 00681, USA; E-Mails: [email protected] (E.L.); [email protected] (K.C.-C.); [email protected] (J.R.); [email protected] (M.O.-M.); [email protected] (J.I.); [email protected] (V.G.); [email protected] (J.A.R.); [email protected] (M.C.-R.) 2 Pittsburgh Supercomputing Center, 300 S. Craig Street, Pittsburgh, PA 15213, USA; E-Mail: [email protected] 3 Department of Pharmacology and Toxicology, Ponce School of Medicine, PO Box 700, Ponce, PR 00732, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-787-840-2575 (ext. 2198). Academic Editor: Shu-Kay Ng Received: 22 February 2015 / Accepted: 13 May 2015 / Published: 28 May 2015 Abstract: Establishing how a series of potentially important genes might relate to each other is relevant to understand the origin and evolution of illnesses, such as cancer. High-throughput biological experiments have played a critical role in providing information in this regard.
    [Show full text]
  • Genetic Abnormalities in Pancreatitis: an Update on Diagnosis, Clinical Features, and Treatment
    diagnostics Review Genetic Abnormalities in Pancreatitis: An Update on Diagnosis, Clinical Features, and Treatment Mitsuyoshi Suzuki 1,* , Kei Minowa 1 , Satoshi Nakano 1, Hiroyuki Isayama 2 and Toshiaki Shimizu 1 1 Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan; [email protected] (K.M.); [email protected] (S.N.); [email protected] (T.S.) 2 Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; [email protected] * Correspondence: [email protected] Abstract: Several pancreatitis susceptibility genes have been identified to date. A relationship between a mutation in the cationic trypsinogen (protease serine 1, PRSS1) gene and hereditary pancreatitis (HP) was first identified in 1996. Currently, HP has been defined as either two or more individuals within a family exhibiting pancreatitis for two or more generations, or pancreatitis linked to mutation of the PRSS1 gene. In 2000, a mutation in the serine protease inhibitor gene (Kazal type 1: SPINK1) was reported to be related to sporadic pancreatitis of unknown etiology. This paper reviews and summarizes the current published data on the pancreatitis susceptibility genes, mainly PRSS1 and SPINK1 genes, and introduces a diagnostic and therapeutic approach for dealing with patients with these gene mutations. Patients with these genetic predispositions, both children and adults, have often been initially diagnosed with idiopathic acute pancreatitis, in approximately 20–50% of pediatric cases and 28–80% of adult cases. In such patients, where the etiology is unknown, genetic testing, which requires pre-test and post-test genetic counselling, may prove helpful.
    [Show full text]
  • PRSS2 Stimulates Tumor Growth by Remodeling the TME Via Repression of Tsp1
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.23.436667; this version posted March 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. PRSS2 stimulates tumor growth by remodeling the TME via repression of Tsp1 Lufei Sui1,2*, Suming Wang1,2*#, Debolina Ganguly3, Tina El Rayes4,5,6, Cecilie Askeland7,8, Astrid Børretzen7,8, Danielle Sim1, Ole Johan Halvorsen7,8, Gøril Knutsvik7,8, Sura Aziz7,8, Svein Haukaas9, William D Foulkes10,11, Diane R. Bielenberg1,2, Arturas Ziemys12, Vivek Mittal4,5,6, Rolf A. Brekken3,7, Lars A. Akslen7,8, and Randolph S. Watnick1,2,7,8,13 1 Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115 2 Department of Surgery, Harvard Medical School, Boston, MA 02115 3 Hamon Center for Therapeutic Oncology Research and Department of Surgery, UT Southwestern, Dallas, TX 4 Department of Cardiothoracic Surgery, Weill Cornell Medical College, NY, NY 5 Department of Cell and Developmental Biology, Weill Cornell Medical College, NY, NY 6 Neuberger Berman Lung Cancer Center, Weill Cornell Medical College, NY, NY 7 Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway 8 Department of Pathology, Haukeland University Hospital, Bergen, Norway 9 Department of Urology, Haukeland University Hospital, Bergen, Norway 10 Cancer Axis, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada 11 Department of Human Genetics, McGill University, Montreal, Quebec, Canada 12 The program in Mathematics in Medicine, Houston Methodist Research Institute, Houston, TX 13 To whom correspondence should be addressed ([email protected]) * These authors contributed equally # Current address: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.03.23.436667; this version posted March 31, 2021.
    [Show full text]
  • PRSS2) Variant Protects Against Chronic Pancreatitis
    LETTERS A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis Heiko Witt1,2,39, Miklo´s Sahin-To´th3,39, Olfert Landt4, Jian-Min Chen5, Thilo Ka¨hne6, Joost PH Drenth7, Zolta´n Kukor3, Edit Szepessy3, Walter Halangk8, Stefan Dahm9, Klaus Rohde9, Hans-Ulrich Schulz8,Ce´dric Le Mare´chal5, Nejat Akar10, Rudolf W Ammann11, Kaspar Truninger11,12, Mario Bargetzi13, Eesh Bhatia14, Carlo Castellani15, Giulia Martina Cavestro16, Milos Cerny17, Giovanni Destro-Bisol18, Gabriella Spedini18, Hans Eiberg19, Jan B M J Jansen7, Monika Koudova20, Eva Rausova20, Milan Macek Jr20,Nu´ria Malats21, Francisco X Real21, Hans-Ju¨rgen Menzel22, Pedro Moral23, Roberta Galavotti24, Pier Franco Pignatti24, Olga Rickards25, Julius Spicak26, Narcis Octavian Zarnescu27, Wolfgang Bo¨ck28, Thomas M Gress28, Helmut Friess29, Johann Ockenga30, Hartmut Schmidt30,31, Roland Pfu¨tzer32, Matthias Lo¨hr32, Peter Simon33, Frank Ulrich Weiss33, Markus M Lerch33, Niels Teich34, Volker Keim34, Thomas Berg1, Bertram Wiedenmann1, Werner Luck2, David Alexander Groneberg2, Michael Becker35, Thomas Keil36, Andreas Kage37, Jana Bernardova1,2, Markus Braun1,2, Claudia Gu¨ldner1,2, Juliane Halangk1, Jonas Rosendahl2,34, Ulrike Witt38, Matthias Treiber1,2, Renate Nickel2 & Claude Fe´rec5 http://www.nature.com/naturegenetics Chronic pancreatitis is a common inflammatory disease overrepresented in control subjects: G191R was present of the pancreas. Mutations in the genes encoding cationic in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%)
    [Show full text]