DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2015/0050646A1 Hageman (43) Pub

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2015/0050646A1 Hageman (43) Pub US 2015.0050646A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0050646A1 Hageman (43) Pub. Date: Feb. 19, 2015 (54) METHODS AND REAGENTS FOR (60) Provisional application No. 60/840,073, filed on Aug. TREATMENT AND DAGNOSS OF 23, 2006, provisional application No. 60/831,018, VASCULARDISORDERS AND AGE-RELATED filed on Jul. 13, 2006. MACULAR DEGENERATION Publication Classification (71) Applicant: University of Iowa Research Foundation, Iowa City, IA (US) (51) Int. Cl. CI2O I/68 (2006.01) (72) Inventor: Gregory S. Hageman, Salt Lake City, (52) U.S. Cl. UT (US) CPC ........ CI2O I/6883 (2013.01); C12O 2600/1 12 (2013.01) (73) Assignee: University of Iowa Research USPC ......................................... 435/6.11: 435/6.12 Foundation, Iowa City, IA (US) (57) ABSTRACT (21) Appl. No.: 14/279,235 Disclosed are screening methods for determining a human Subject's propensity to develop a vascular disorder and/or (22) Filed: May 15, 2014 age-related macular degeneration (AMD), therapeutic or pro phylactic compounds for treating disease or inhibiting its O O development, and methods of treating patients to alleviate Related U.S. Application Data SN of the disease, prevent or E. its onset, or inhibit (63) Continuation of application No. 12/954.425, filed on its progression. The inventions are based on the discovery that Nov. 24, 2010, now abandoned, which is a continu persons with a genome having a deletion of the CFHR-1 ation of application No. 1 1/894,667, filed on Aug. 20, and/or CFHR-3 gene, which normally lie on human chromo 2007, now Pat. No. 7,867,727, which is a continuation some 1 between DNA encoding CFH and CFHR-4, are at of application No. PCT/US07/73514, filed on Jul. 13, reduced risk of developing AMD, and elevated risk of devel 2007. oping vascular disease Such as aneurysm. Patent Application Publication Feb. 19, 2015 Sheet 1 of 16 US 2015/0050646A1 @@@@@ @@@@@ @@@@@ @@@@ @@@@@@@@@ Patent Application Publication Feb. 19, 2015 Sheet 2 of 16 US 2015/0050646 A1 CFHR3 CFHR1 CFHR4 CFHR2 CFHR5 --ILLI-I-I-IIIll-ll-Fil-ll-I-III-lill-L-Lill- --- - - - - - A B A' C D B" A" C" D'B"D" 50kb. FIG. 2 Patent Application Publication Feb. 19, 2015 Sheet 3 of 16 US 2015/0050646 A1 Cs a cu N C C Co s go cC N co Od co sea CO & raS J S Sd S N. N. CFHR2 Patent Application Publication Feb. 19, 2015 Sheet 4 of 16 US 2015/0050646 A1 Patent Application Publication Feb. 19, 2015 Sheet 5 of 16 US 2015/0050646 A1 Patent Application Publication Feb. 19, 2015 Sheet 7 of 16 US 2015/0050646 A1 CFHR1 AA seq. 39 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 38 CHFR3 AA seq. l40 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 39 H Factor AA seq. 600 GFTIVGPNSVQCYHFGLSPDLPICKEQVQSCGPPPELLNGNVKEKTKEEY 649 CFHR1 AA seq. 39 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 138 CHFR3 AA seq. 140 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 39 H. Factor AA seq. 650 GHSEVVEYYCNPRFLMKGPNKIQCVDGEWTTLPVCIVEESTCGDIPELEH 699 CFHR1 AA seq. 1.39 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - w w is - - - - 1.38 CHFR3 AA seq. 140 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - w w w - - - - - - a sa w - - - - 1.39 H Factor AA seq. 700 GWAQLSSPPYYYGDSVEFNCSESFTMIGHRSITCIHGVWTOLPQCVAIDK 749 CFHR1 AA seq. 39 - - - - - - - - - - - - - - - r - - - - - - - - - - - - r - - - - - - - - - - - - - - - - - - - - - 138 CHFR3 AA seq. 1 4 0 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 39 H Factor AA seq. 750 LKKCKSSNLIII.EEHLKNKKEFDHNSNIRYRCRGKEGWIHTVCINGRWDP 799 CFHR1 AA seq. 39 - - KCRST- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 43 CHFR3 AA seq. 4 O - mRCR- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 143 k H Factor AA seq 800 EVNCSMAQIQLCPPPPQIPNSHNMTTTLNYRDGEKVSVLCQENYLIQEGE 849 CFHR1 AA seq. 144 - - - - - - - - - - - - - - - - - - - - - - - - - - - - or n as a sm - - - m n n n m r - m - - - - - 143 CHFR3 AA seq. 44 in - - - - - - - - - - - - - - - - - - - - - - - - - n w w w w we m r n w mm mm mm r - - - - - - 143 H. Factor AA seq. 850 EITCKDGRWQSIPLCVEKIPCSQPPQIEHGTINSSRSSQESYAHGTKLSY 899 CFHR1 AA seq. 144 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 143 CHFR3 AA seq. 144 - - - - - - - - - - - - - - - - - - - - - - - - - - m r n - - - - - - - - - - - - - - - - - - - - - 143 H Factor AA seq. 900 TCEGGFRISEENETTCYMGKWSSPPQCEGLPCKSPPEISHGVWAHMSDSY 949 CFHR1 AA seq. 144 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3.43 CHFR3 AA seq. 44 - - - - - - - - - - - - - - - - - - - - - - - - - - - m r - - - - - - - - - - - - - - - - - - - - - 1.43 H. Factor AA seq. 950 QYGEEVTYKCFEGFGIDGPAIAKCLGEKWSHPPSCIKTDCLSLPSFENAI 999 CFHRl AA seq. 44 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 43 CHFR3 AA seq. 144 m - - - - - - - - m n - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - n w - - - - - - 43 H Factor AA seq 1000 PMGEKKDVYKAGEQVTYTCATYYKMDGASNVTCINSRWTGRPTCRDTSCV 1049 CFHR1 AA seq., 144 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - r n re a m - - - m r n - - - DTSCW 1.48 CHFR3 AA seq. 144 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - was - - - - - - - - - DRTCS 148 H Factor AA seq. 1050 NPPTVQNAYIVSRQMSKYPSGERVRYQCRSPYEMFGDEE- - -WMCLNGNW 1096 CFHR1 AA seq. 149 NPPTVQNAYIVSRQMSKYPSGERVRYQCRSPYEMFGDEE - - -WMCLNGNW 95 CHFR3 AA seq. 149 KSDIEIENGFISESSSIYILNKEIQYKCKPGYATADGNSSGSITCLRNGW 1.98 .k * k . k.k. k . k. FIG. 6 (cont.) Patent Application Publication Feb. 19, 2015 Sheet 9 of 16 US 2015/005064.6 A1 H. Factor IRNA 1 ATGAGACTCTAGCAAAGATTATTTGCCTTATGTTATGGGCTATTTGTGT 5 O CEHR1 mRNA l O CFR3 mRNA 1. O H Factor mRNA 5 AGCAGAAGACGCAATGAACTTCCTCCAAGAAGAAATACAGAAATCGA 1.00 CFHR1 mRNA 1. O CFHR3 mRNA 1. O H. Factor mRNA 101 CAGGTTCCTGGTCTGACCAAACAATCCAGAAGGCACCCAGGCTATCTAT 150 CFHR mRNA l O CFHR3 mRNA 1. O H. Factor in RNA 15 AAATGCCGCCCTGGATATAGATCTCTTGGAAATGTAATAATGGTATGCAG 200 CFHR1 mRNA s 1. O CFHR3 mRNA 1. O H Factor mRNA 201 GAAGGGAGAATGGGTTGCTCTTAATCCATAAGGAAATGTCAGAAAAGGC 250 CFHR mRNA 1. O CFHR3 tRNA 1. O H Factor RNA 251 CCTGTGGACATCCGGAGATACTCCTTTTGGTACTTTTACCCTTACAGGA 300 CFHR RNA 1. O CFHR3 mRNA O H Factor mRNA 30, GGAAAGTGTTTGAATATGGGTAAAAGCTGTGTATACATGTAATGAGGG 350 CFHR1 mRNA O CFHR3 mRNA 1. O H Factor RNA 35 GTACAATTGCTAGGTGAGATTAATTACCGTGAATGIGACACAGATGGAT 400 CFHR1 mRNA O CEHR3 mRNA 1. O H. Factor RNA 40 GGACCAATGATATTCCTATATGGAAGTTGTGAAGTGTTTACCAGTGACA 450 CFHR mRNA - O CFHR3 RNA 1. O H. Factor RNA A 5 GCACCAGAGAATGGAAAAATTGTCAGTAGGCAATGGAACCAGATCGGGA 500 CFHR1 mRNA O CFHR3 mRNA 1. O H. Factor mRNA 5 O1. ATACCATTTTGGACAAGCAGTACGGTTTGTATGTAACTCAGGCTACAAGA 550 CEHR1 RNA O CEHR3 mRNA O FIG. 7 Patent Application Publication Feb. 19, 2015 Sheet 10 of 16 US 2015/0050646 A1 Factor RNA GAAGGAGAGAAGAAATGCATGTCAGACGATGGTTTGGAGAAA CFHR mRNA CFR3 mRNA H Factor mRNA GAGAAACCAAAGTGGGGAAAIFICAGCAAAICCCCAGAGTATAAA CBER RNA CEHR3 RNA H. Factor RNA GGACCCTATATCTCAGAAGATTATATAAGGAGAAGAACGATTC CFHR mRNA CFER3 mRNA Factor RNA AAATAAATGTAACATGGGTTATGAATACAGTGAAAGAGGAGAIGCTGTA CFER RNA CEHR3 rRNA Factor mRNA TGCACTGAATCGGATGGCGTCCGTTGCCTTCATGTGAAGAAAAATCATG CFER1 mRNA CFHR3 RNA H Factor mRNA TGATAACCTATATCCAAATGGTGACTACCACCTTAAGGATAAAC CFHR mRNA CEHR3 mRNA H Factor RNA ACAGAACTGGAGATGAAATCACGTACCAGTGTAGAAATGGTTTATCC CFHR rara CEHR3 RNA Factor mRNA GCAACCCGGGGAAAACAGCCAAATGCACAAGTACTGGCGGAACCTGC CFHR mRNA CFHR3 rRNA H Factor RNA TCCGAGATGTACCTTGAAAccTTGTGATTATCCAGACATTAAACATGGAG CEHR mRNA CFR3 mRNA H Factor RNA O O. GCIAEATCAGAGAAAEGCGTAGACCATACTTTCCAGTAGCGTAGGA CFR in RNA CEHR3 rRNA H Factor RNA AAAAACCCTATACTGTGATGAACATTTTGAGACCCGTCAGGAAG CFHR RNA CFR3 mRNA FIG. 7 (cont.) Patent Application Publication Feb. 19, 2015 Sheet 11 of 16 US 2015/0050646 A1 H Factor mRNA TTACTGGGATCACATTCATGCACACAAGATGGATGGTCGCCAGCAGTAC CFHR mRNA CEHER3 mRNA H Facto mRNA CATGCCTCAGAAAATGTTATTTTCCTTATTFGGAAAATGGATATAATCAA CFHR1 IRNA CFHR3 mRNA H. Factor mRNA AATCATGGAAGAAAGTGTACAGGGAAATCATAGACGTTGCCTGCCA CFHR1 mRNA CFR3 RNA H Factor mRNA TCCTGGCTAcGCTCTCCAAAAGCGCAGACCACAGTTACATGTATGGAGA CFHR1 IRNA CFHR3 RNA H. Factor RNA ATGGCTGGTCTCCTACTCCCAGATGCATCCGTGTCAAAACATGTTCCAAA CFHR1 mRNA CFHR3 mRNA H Factor mRNA TCAAGATAGATATTGAGAATGGGTTTATTTCTGAATCTCAGATACATA CFHR1 mRNA CFHR3 mRNA H Factor RNA TGCCTTAAAAGAAAAAGCGAAATATCAATGCAAACTAGGATATGTAACAG CEHR1 IRNA CFR3 mRNA H. Factor mRNA CAGATGGTGAAACACAGGATCAATTAGATGTGGGAAAGATGGATGGTCA CEHR RNA CFR3 mRNA H Factor mRNA GCTCAACCCACGTGCATTAAATCTTGTGATACCCAGTATTTAGAATGC CFBR triNA CFHR3 mRNA H Factor RNA CAGAACTAAAAATGACTTCACATGGTTTAAGCTGAATGACACATTGGACT CFHR1 mRNA CFHR3 mRNA H Factor RNA ATGAAGCCATGAGGTTATGAAAGCAATACTGGAAGCACCACTGGTTCC CFHR mRNA CFHR3 mRNA FIG. 7 (cont.) Patent Application Publication Feb. 19, 2015 Sheet 12 of 16 US 2015/0050646 A1 H Factor RNA ATAGTGTGTGGTACAATGGTTGGTCTGATTACCCAAGTATGAAAG CEHR1, RNA CFR3 mRNA Factor mRNA AGAATGCGAACTTCCTAAAATAGATGACACTAGTCCCTGACGCAAGA CEHR mRNA CFR3 mRNA H. Factor mRNA AAGACCAGAAAAGGGAGAGGGIGAAATCCCTGCAAACCAGGA CFHR1 mRNA CFHR3 mRNA H. Factor mRNA TTTACAATAGTTGGACCTAATTCCGTCAGIGCTACCACTTTGGATEGIC CEHR RNA CER3 mRNA H. Factor RNA CCTGACCTCCCAAEATGTAAAGAGCAAGTACAATCATGTGGTCCACCC CFHR1 mRNA
Load more

Recommended publications
  • Biomarker Discovery for Chronic Liver Diseases by Multi-Omics
    www.nature.com/scientificreports OPEN Biomarker discovery for chronic liver diseases by multi-omics – a preclinical case study Daniel Veyel1, Kathrin Wenger1, Andre Broermann2, Tom Bretschneider1, Andreas H. Luippold1, Bartlomiej Krawczyk1, Wolfgang Rist 1* & Eric Simon3* Nonalcoholic steatohepatitis (NASH) is a major cause of liver fbrosis with increasing prevalence worldwide. Currently there are no approved drugs available. The development of new therapies is difcult as diagnosis and staging requires biopsies. Consequently, predictive plasma biomarkers would be useful for drug development. Here we present a multi-omics approach to characterize the molecular pathophysiology and to identify new plasma biomarkers in a choline-defcient L-amino acid-defned diet rat NASH model. We analyzed liver samples by RNA-Seq and proteomics, revealing disease relevant signatures and a high correlation between mRNA and protein changes. Comparison to human data showed an overlap of infammatory, metabolic, and developmental pathways. Using proteomics analysis of plasma we identifed mainly secreted proteins that correlate with liver RNA and protein levels. We developed a multi-dimensional attribute ranking approach integrating multi-omics data with liver histology and prior knowledge uncovering known human markers, but also novel candidates. Using regression analysis, we show that the top-ranked markers were highly predictive for fbrosis in our model and hence can serve as preclinical plasma biomarkers. Our approach presented here illustrates the power of multi-omics analyses combined with plasma proteomics and is readily applicable to human biomarker discovery. Nonalcoholic fatty liver disease (NAFLD) is the major liver disease in western countries and is ofen associated with obesity, metabolic syndrome, or type 2 diabetes.
    [Show full text]
  • Complement Factor H Deficiency and Endocapillary Glomerulonephritis Due to Paternal Isodisomy and a Novel Factor H Mutation
    Genes and Immunity (2011) 12, 90–99 & 2011 Macmillan Publishers Limited All rights reserved 1466-4879/11 www.nature.com/gene ORIGINAL ARTICLE Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation L Schejbel1, IM Schmidt2, M Kirchhoff3, CB Andersen4, HV Marquart1, P Zipfel5 and P Garred1 1Department of Clinical Immunology, Laboratory of Molecular Medicine, Rigshospitalet, Copenhagen, Denmark; 2Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark; 3Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark; 4Department of Pathology, Rigshospitalet, Copenhagen, Denmark and 5Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (o6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome.
    [Show full text]
  • Complement Factor H Related Proteins (Cfhrs)
    G Model MIMM-4208; No. of Pages 11 ARTICLE IN PRESS Molecular Immunology xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Molecular Immunology jo urnal homepage: www.elsevier.com/locate/molimm Review Complement factor H related proteins (CFHRs) a,∗ a b,c b,d,e Christine Skerka , Qian Chen , Veronique Fremeaux-Bacchi , Lubka T. Roumenina a Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany b Centre de Recherche des Cordeliers, INSERM UMRS 872, Paris, France c Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France d Université Paris Descartes Sorbonne Paris-Cité, Paris, France e Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France a b s t r a c t a r t i c l e i n f o Factor H related proteins comprise a group of five plasma proteins: CFHR1, CFHR2, CFHR3, CFHR4 and Article history: CFHR5, and each member of this group binds to the central complement component C3b. Mutations, Received 1 May 2013 genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with a Accepted 8 May 2013 Available online xxx number of diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3 glomerulonephritis (C3GN), dense deposit disease (DDD) and CFHR5 nephropathy), IgA nephropathy, age related macular degeneration (AMD) and systemic lupus erythematosus (SLE). Although complement regulatory functions were attributed to most of the members of the CFHR protein family, the precise role of each CFHR protein in complement activation and the exact contribution to disease pathology is still unclear.
    [Show full text]
  • New Functional and Structural Insights from Updated Mutational Databases for Complement Factor H, Factor I, Membrane Cofactor Protein and C3
    Biosci. Rep. (2014) / 34 / art:e00146 / doi 10.1042/BSR20140117 New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3 Elizabeth Rodriguez*1, Pavithra M. Rallapalli*1, Amy J. Osborne* and Stephen J. Perkins*2 *Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K. Synopsis aHUS (atypical haemolytic uraemic syndrome), AMD (age-related macular degeneration) and other diseases are associated with defective AP (alternative pathway) regulation. CFH (complement factor H), CFI (complement factor I), MCP (membrane cofactor protein) and C3 exhibited the most disease-associated genetic alterations in the AP.Our interactive structural database for these was updated with a total of 324 genetic alterations. A consensus structure for the SCR (short complement regulator) domain showed that the majority (37 %) of SCR mutations occurred at its hypervariable loop and its four conserved Cys residues. Mapping 113 missense mutations onto the CFH structure showed that over half occurred in the C-terminal domains SCR-15 to -20. In particular, SCR-20 with the highest total of affected residues is associated with binding to C3d and heparin-like oligosaccharides. No clustering of 49 missense mutations in CFI was seen. In MCP, SCR-3 was the most affected by 23 missense mutations. In C3, the neighbouring thioester and MG (macroglobulin) domains exhibited most of 47 missense mutations. The mutations in the regulators CFH, CFI and MCP involve loss-of-function, whereas those for C3 involve gain-of-function. This combined update emphasizes the importance of the complement AP in inflammatory disease, clarifies the functionally important regions in these proteins, and will facilitate diagnosis and therapy.
    [Show full text]
  • Molecular and Epigenetic Features of Melanomas and Tumor Immune
    Seremet et al. J Transl Med (2016) 14:232 DOI 10.1186/s12967-016-0990-x Journal of Translational Medicine RESEARCH Open Access Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab‑based immunotherapy in metastatic patients Teofila Seremet1,3*† , Alexander Koch2†, Yanina Jansen1, Max Schreuer1, Sofie Wilgenhof1, Véronique Del Marmol3, Danielle Liènard3, Kris Thielemans4, Kelly Schats5, Mark Kockx5, Wim Van Criekinge2, Pierre G. Coulie6, Tim De Meyer2, Nicolas van Baren6,7 and Bart Neyns1 Abstract Background: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10–15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing indi- vidualized treatment strategies. Methods: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). Results: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8+ and PD-L1+ cells than NB tumors.
    [Show full text]
  • Epistatic Interactions of Genetic Loci Associated with Age-Related
    www.nature.com/scientificreports OPEN Epistatic interactions of genetic loci associated with age‑related macular degeneration Christina Kiel1,3, Christoph A. Nebauer1,3, Tobias Strunz1,3, Simon Stelzl1 & Bernhard H. F. Weber 1,2* The currently largest genome‑wide association study (GWAS) for age‑related macular degeneration (AMD) defnes disease association with genome‑wide signifcance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD‑associated variants that reveal joint efects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifcally the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high‑risk AMD. We identifed genetic variant combinations correlating signifcantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defnes novel targets and allows prioritizing further functional work into AMD pathobiology. A frst successful genome-wide association study (GWAS) was reported in 2005 and identifed with genome- wide signifcance genetic variants at the CFH locus associated with age-related macular degeneration (AMD), a complex disease which is a frequent cause of progressive vision loss in the elderly population 1. Since then, the list of AMD-associated genetic variation has grown exponentially, presently bringing the total to 52 independent common and rare variants across 34 chromosomal loci2.
    [Show full text]
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
    biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.
    [Show full text]
  • A Genome-Wide Association Study Identifies Key Modulators of Complement Factor H Binding to Malondialdehyde-Epitopes
    A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes Lejla Alica,b,c,1, Nikolina Papac-Milicevica,b,1,2, Darina Czamarad, Ramona B. Rudnicke, Maria Ozsvar-Kozmaa,b, Andrea Hartmanne, Michael Gurbisza, Gregor Hoermanna,f, Stefanie Haslinger-Huttera, Peter F. Zipfele,g, Christine Skerkae, Elisabeth B. Binderd, and Christoph J. Bindera,b,2 aDepartment of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; bResearch Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; cDepartment of Medical Biochemistry, Faculty of Medicine, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina; dDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany; eDepartment of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany; fCentral Institute for Medical and Chemical Laboratory Diagnosis, University Hospital Innsbruck, 6020 Innsbruck, Austria; and gInstitute for Microbiology, Friedrich Schiller University, 07743 Jena, Germany Edited by Thaddeus Dryja, Harvard Medical School, Boston, MA, and approved March 17, 2020 (received for review August 12, 2019) Genetic variants within complement factor H (CFH), a major head-to-tail fashion. Moreover, its splice variant factor H-like alternative complement pathway regulator, are associated with protein 1 (FHL-1), consisting of the first seven SCRs of CFH, the development of age-related
    [Show full text]
  • Complement System in the Pathogenesis of Benign Lymphoepithelial Lesions of the Lacrimal Gland
    RESEARCH ARTICLE Complement System in the Pathogenesis of Benign Lymphoepithelial Lesions of the Lacrimal Gland Jing Li1,2, Xin Ge1, Xiaona Wang1,2, Xiao Liu1, Jianmin Ma1* 1 Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China, 2 Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China * [email protected] Abstract Objective We aimed to examine the potential involvement of local complement system gene expres- sion in the pathogenesis of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. OPEN ACCESS Citation: Li J, Ge X, Wang X, Liu X, Ma J (2016) Methods Complement System in the Pathogenesis of Benign We collected data from 9 consecutive pathologically confirmed patients with BLEL of the Lymphoepithelial Lesions of the Lacrimal Gland. PLoS ONE 11(2): e0148290. doi:10.1371/journal. lacrimal gland and 9 cases with orbital cavernous hemangioma as a control group, and pone.0148290 adopted whole genome microarray to screen complement system-related differential Editor: Qiang WANG, Sichuan University, CHINA genes, followed by RT-PCR verification and in-depth enrichment analysis (Gene Ontology analysis) of the gene sets. Received: September 26, 2015 Accepted: January 15, 2016 Results Published: February 5, 2016 The expression of 14 complement system-related genes in the pathologic tissue, including Copyright: © 2016 Li et al. This is an open access C2, C3, ITGB2, CR2, C1QB, CR1, ITGAX, CFP, C1QA, C4B|C4A, FANCA, C1QC, C3AR1 article distributed under the terms of the Creative and CFHR4, were significantly upregulated while 7 other complement system-related Commons Attribution License, which permits genes, C5, CFI, CFHR1|CFH, CFH, CD55, CR1L and CFD were significantly downregulated unrestricted use, distribution, and reproduction in any medium, provided the original author and source are in the lacrimal glands of BLEL patients.
    [Show full text]
  • The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's
    G C A T T A C G G C A T genes Article The Impact of Complement Genes on the Risk of Late-Onset Alzheimer’s Disease Sarah M. Carpanini 1,2,† , Janet C. Harwood 3,† , Emily Baker 1, Megan Torvell 1,2, The GERAD1 Consortium ‡, Rebecca Sims 3 , Julie Williams 1 and B. Paul Morgan 1,2,* 1 UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff, CF24 4HQ, UK; [email protected] (S.M.C.); [email protected] (E.B.); [email protected] (M.T.); [email protected] (J.W.) 2 Division of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Cardiff, CF14 4XN, UK 3 Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK; [email protected] (J.C.H.); [email protected] (R.S.) * Correspondence: [email protected] † These authors contributed equally to this work. ‡ Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report. A full list of GERAD1 investigators and their affiliations is included in Supplementary File S1. Abstract: Late-onset Alzheimer’s disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver Citation: Carpanini, S.M.; Harwood, effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential.
    [Show full text]
  • The Analysis of Risk Factors for Diabetic Nephropathy Progression and The
    Wang et al. J Transl Med (2019) 17:264 https://doi.org/10.1186/s12967-019-2016-y Journal of Translational Medicine RESEARCH Open Access The analysis of risk factors for diabetic nephropathy progression and the construction of a prognostic database for chronic kidney diseases Gang Wang1,2, Jian Ouyang3, Shen Li2, Hui Wang2, Baofeng Lian3, Zhihong Liu1,2* and Lu Xie3* Abstract Background: Diabetic nephropathy (DN) afects about 40% of diabetes mellitus (DM) patients and is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) all over the world, especially in high- and middle-income countries. Most DN has been present for years before it is diagnosed. Currently, the treatment of DN is mainly to prevent or delay disease progression. Although many important molecules have been discovered in hypothesis-driven research over the past two decades, advances in DN management and new drug develop- ment have been very limited. Moreover, current animal/cell models could not replicate all the features of human DN, while the development of Epigenetics further demonstrates the complexity of the mechanism of DN progression. To capture the key pathways and molecules that actually afect DN progression from numerous published studies, we collected and analyzed human DN prognostic markers (independent risk factors for DN progression). Methods: One hundred and ffty-one DN prognostic markers were collected manually by reading 2365 papers published between 01/01/2002 and 12/15/2018. One hundred and ffteen prognostic markers of other four common CKDs were also collected. GO and KEGG enrichment analysis was done using g:Profler, and a relationship network was built based on the KEGG database.
    [Show full text]
  • Genetic Analysis of 400 Patients Refines Understanding And
    BASIC RESEARCH www.jasn.org Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome Fengxiao Bu,1,2 Yuzhou Zhang,2 Kai Wang,3 Nicolo Ghiringhelli Borsa,2 Michael B. Jones,2 Amanda O. Taylor,2 Erika Takanami,2 Nicole C. Meyer,2 Kathy Frees,2 Christie P. Thomas,4 Carla Nester,2,4,5 and Richard J.H. Smith2,4,5 1Medical Genetics Center, Southwest Hospital, Chongqing, China; and 2Molecular Otolaryngology and Renal Research Laboratories, 3College of Public Health, 4Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, and 5Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa ABSTRACT Background Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous. Methods We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggre- gation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant. Results We found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE,andVTN genes. The majority of the significance is contributed by variants with a minor allele frequency of ,0.1%.
    [Show full text]