DOCSLIB.ORG

Recent Findings in Genetic Research in AMD

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Recent Findings in Genetic Research in AMD GENETICS OF RETINA FEATURE STORY Recent Findings in Genetic Research in AMD BY ALBERT O. EDWARDS, MD, PHD enes play an important role in age-related Research in Vision and Ophthalmology meeting and are macular degeneration (AMD). In recent years, summarized in this article. researchers have identified genetic variation that contributes to the development of AMD. COPY NUMBER VARIATION GFrom the geneticist’s point of view, AMD is a complex, IN THE REGULATION OF COMPLEMENT late-onset trait in which multiple demographic, environ- ACTIVATION (RCA) REGION mental, and genetic risk factors combine to cause disease. The regulation of complement activation (RCA) Genetic research is a powerful method for identifying the region contains factor H and five related genes called biologic pathways contributing to disease risk. CFH related 1 through 5 (Figure 1). The genes in the Genetic research has identified two major biologic RCA region are sometimes deleted. A combined dele- pathways contributing to the development of AMD. The tion of CFHR3 and CFHR1 occurs in about 15% of peo- first pathway is a branch of the innate immune system ple and has been thought to protect against developing called the alternative pathway of complement. The sec- AMD. However, until recently an accurate method for ond pathway is a segment of DNA on chromosome 10 determining the number of copies in individual subjects called age-related maculopathy susceptibility 2 (ARMS2). was not available. The biologic basis of this second pathway is not yet Katherine Schmid-Kubista, MD, in my laboratory understood, but ARMS2 variants can increase the odds developed a multiplex ligation-dependent probe amplifi- of developing AMD by up to sevenfold. cation (MLPA) assay that allows the determination of the The first major genetic variants consistently associated exact number of copies of the CFHR3 and CFHR1 genes.2 with AMD were found in the complement factor H gene The assay was used to genotype 252 subjects with and (CFH).1 Factor H is an inhibitor of activation of the alterna- 249 without AMD to determine whether the number of tive pathway of complement. Candidate gene studies in copies of these genes altered the risk of developing AMD. this pathway subsequently identified variation in the com- We found four combinations of copy number varia- plement component 2, factor B, component 3, and factor I tions. Deletions of both CFHR3 and CFHR1 was identi- genes. Each of these genes encodes proteins important in fied in 14% of chromosomes, deletion of only CFHR3 was our body’s response to infection and damage. seen in 0.4%, deletion of only CFHR1 in 1.1%, and dupli- Genetic variation in other pathways, including the clas- cation of CFHR1 in 0.1%. sical complement pathway (SERPING1), danger-sensing Deletion of both copies of CFHR3/CFHR1 was found pathways (TLR4, TLR3), lipid pathway (ApoE), immune to decrease the odds of having AMD eightfold. response pathways (HLA, KIR), and the mitochondrial However, combined deletion of CFHR3/CFHR1 was genome, have been reported. Most have not been ade- always found on the same chromosome as a protective quately replicated, except for the ApoE2 variant protect- form of CFH. We were unable to demonstrate an inde- ing against AMD. pendent effect of the combined deletion or a difference Research into the genetic roots of AMD in our labora- in subjects with or without the risk histidine amino acid tory has continued to focus on these and other impor- at position 402 in factor H. tant loci. A number of papers from us and our collabora- We concluded that deletion of CFHR3 and CFHR1 pro- tors were presented at this year’s Association for tected against the development of AMD at least in part 78 IRETINA TODAYISEPTEMBER 2009 GENETICS OF RETINA FEATURE STORY Figure 1. Variation in the number of copies of genes within the regulation of complement activation (RCA) region.The location bar across the top shows the base pair location on chromosome 1. Note that the RCA region is located within band 31.3 of chro- mosome 1. CFH was the original gene, and the CFHR genes arose through duplication during evolution.The bottom panel shows copy number changes observed in a variety of genome-wide genetic studies. Note that deletions (blue) in the CFHR3/CFHR1 region are common, as are deletions of CFHR4.The image was downloaded from the Database of Genomic Variants at http://projects.tcag.ca. because the deletion tagged protective forms of CFH. We changes in complement genes alter the regulation of the have now developed an assay that determines the copy alternative pathway of complement activation in human number of all genes in the RCA region and will be able to tissue and blood. Laura Hecker, PhD, of our laboratory look at the impact of the common CFHR4 deletion presented a study of how these genetic variants altered (Figure 1) on AMD risk. complement protein levels and activation in blood from patients with and without AMD.4 These studies were GENOME-WIDE ASSOCIATION STUDY performed in collaboration with the group of Martin In order to identify novel genetic variation contributing Oppermann, PhD, in Germany. to AMD, we performed a genome-wide association study.3 We confirmed the increased complement activation in This study was led by Anand Swaroop, PhD, Gonçalo AMD patients compared with controls that was first Abecasis, PhD, Dwight Stambolian, MD, and myself. We reported by Dr. Oppermann’s group at ARVO in 2008. genotyped more than 370,000 single nucleotide polymor- We went on to show that complement activation in the phisms (SNPs) in 2,136 unrelated white patients with AMD blood of humans is under genetic control. Further, the and 1,138 white control subjects using the HumanCNV370 genetic risks for AMD that are found in regions of com- Duo BeadChip (Illumina, San Diego, CA). Using resources plement proteins involved in regulation of complement from the HapMap consortium we predicted the geno- activation in blood increased complement activation in types at about 2.5 million additional common SNPs. all subjects. Genetic variants located in regions involved This study confirmed previously reported associa- in tissue regulation of complement activation did not tions of known genetic variants with AMD, including alter complement levels in blood. SNPs at CFH, C2/BF, C3, and ARMS2. We also replicated We concluded that fluid phase inhibition of comple- the association between CFI and AMD for the first time. ment activation is decreased in subjects with AMD. Two additional pathways contributing to AMD were This leads to increased activation of complement in also discovered, providing insight into the pathogenesis the blood of AMD subjects. We believe that comple- of AMD. These will be published later this year. ment activation in the blood could mediate some of the effects of lifestyle choices such as diet and smoking COMPLEMENT ACTIVATION IS INCREASED and contribute to the development of AMD. This work IN THE BLOOD OF AMD PATIENTS is under revision and is expected to be published later We have become interested in how the genetic this year. SEPTEMBER 2009 IRETINA TODAYI 79 GENETICS OF RETINA FEATURE STORY CONCLUSIONS in Vision and Ophthalmology; May 5, 2009; Fort Lauderdale, FL. Genetic risks account for about 80% of the risk of developing AMD. Modifiable lifestyle and environmen- tal factors such as diet, exercise, obesity, and smoking also alter the risk of developing AMD. Most studies have observed that these are independent risks, illus- trating the importance of educating your patients about the modifiable risks. All of the genetic risks contribute to the formation of the maculopathy (inflammatory deposits in the outer retina such as drusen) that characterizes AMD. Although some reports have suggested that specific genetic variants contribute to complications of AMD (geographic atrophy, exudation), the majority of studies have not observed such effects. With the exception of smoking, which appears to exert a major impact on progression to exudation, the known risks appear to increase the risk of having the maculopathy of AMD. The most important risk for developing the complications of AMD is the burden of the maculopathy, namely the drusen and pigment changes that you see in your patients. While genetic research will continue to shed light on the mechanisms of disease, it is important that we counsel patients on the modifiable risk factors, such as smoking, exercise, and diet. Patients can reduce their risk for developing both the maculopathy and the com- plications of AMD by avoiding tobacco, exercising, and maintaining a healthy diet and body weight. The retina examination we perform is by far the single most important predictor of future vision loss. Thus, our examination and counseling are essential to the care of patients with AMD. ■ Albert O. Edwards, MD, PhD, is at the Mayo Clinic, in Rochester, MN, and at the Oregon Eye Associates and the Institute for Molecular Biology, University of Oregon, in Eugene, OR. Dr. Edwards has no commercial relationships rela- tive to the information discussed in this article. He may be reached at 800-888-2020; or via e-mail at [email protected]. 1. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421-424. 2. Schmid-Kubista KE, Tosakulwong N, Wu Y, et al. Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci. June 24, 2009. [Epub ahead of print] 3. Swaroop A, Chen W, Stambolian D, et al. Genome wide association study (GWAS) of age-related macular degeneration (AMD). Paper presented at: Annual Meeting of Associ- ation for Research in Vision and Ophthalmology; May 4, 2009; Fort Lauderdale, FL.
Load more

Recommended publications
  • Investigation of Modifier Genes Within Copy Number Variations in Rett Syndrome
    See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/51147767 Investigation of modifier genes within copy number variations in Rett syndrome ARTICLE in JOURNAL OF HUMAN GENETICS · MAY 2011 Impact Factor: 2.53 · DOI: 10.1038/jhg.2011.50 · Source: PubMed CITATIONS DOWNLOADS VIEWS 6 89 134 15 AUTHORS, INCLUDING: Dag H Yasui Maria Antonietta Mencarelli University of California, Davis Azienda Ospedaliera Universitaria Senese 30 PUBLICATIONS 1,674 CITATIONS 58 PUBLICATIONS 962 CITATIONS SEE PROFILE SEE PROFILE Francesca Mari Janine M Lasalle Università degli Studi di Siena University of California, Davis 81 PUBLICATIONS 1,658 CITATIONS 98 PUBLICATIONS 3,525 CITATIONS SEE PROFILE SEE PROFILE Available from: Janine M Lasalle Retrieved on: 22 July 2015 Europe PMC Funders Group Author Manuscript J Hum Genet. Author manuscript; available in PMC 2012 January 01. Published in final edited form as: J Hum Genet. 2011 July ; 56(7): 508–515. doi:10.1038/jhg.2011.50. Europe PMC Funders Author Manuscripts Investigation of modifier genes within copy number variations in Rett syndrome Rosangela Artuso1,*, Filomena Tiziana Papa1,*, Elisa Grillo1, Mafalda Mucciolo1, Dag H. Yasui2, Keith W. Dunaway2, Vittoria Disciglio1, Maria Antonietta Mencarelli1, Marzia Pollazzon1, Michele Zappella3, Giuseppe Hayek4, Francesca Mari1, Alessandra Renieri1, Janine M. LaSalle2, and Francesca Ariani1 1 Medical Genetics Section, Biotechnology Department, University of Siena, Italy 2 Medical Microbiology and Immunology, Genome Center, School of Medicine, University of California, Davis, CA, USA 3 Child Neuropsychiatry, Versilia Hospital, Viareggio, Italy 4 Infantile Neuropsychiatry, Siena General Hospital, Italy Abstract MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT).
    [Show full text]
  • 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]
  • Gene Interaction of CFH, ARMS2, and ARMS2&Sol;HTRA1 on the Risk Of
    Eye (2015) 29, 691–698 © 2015 Macmillan Publishers Limited All rights reserved 0950-222X/15 www.nature.com/eye 1,2,3,5 1,2,3,5 4,5 Gene–gene interaction L Huang , Q Meng , C Zhang , LABORATORY STUDY Y Sun1,2,3, Y Bai1,2,3,SLi1,2,3, X Deng1,2,3, of CFH, ARMS2, and B Wang1,2,3,WYu1,2,3, M Zhao1,2,3 and X Li1,2,3 ARMS2/HTRA1 on the risk of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in Chinese population Abstract rs1065489 did not show significant association with nAMD (P40.01), but was strongly Purpose To evaluate the association and associated with PCV in Chinese patients 1Department of interaction of five single-nucleotide (Po0.001). Ophthalmology, Peking polymorphisms (SNPs) in three genes (CFH, University People’s Conclusions In this study, we found that the ARMS2, and ARMS2/HTRA1) with Hospital, Beijing, China interaction of ARMS2 and ARMS2/HTRA1 is neovascular age-related macular degeneration significantly associated with nAMD, and the 2 (nAMD) and polypoidal choroidal Key Laboratory of Vision interaction of CFH and ARMS2 is pronounced vasculopathy (PCV) in Chinese population. Loss and Restoration, in PCV development in Chinese population. Ministry of Education, Methods A total of 300 nAMD and 300 PCV Eye 29, – Beijing, China patients and 301 normal subjects participated (2015) 691 698; doi:10.1038/eye.2015.32; published online 13 March 2015 in the present study. The allelic variants of 3Department of Abdominal rs800292, rs2274700, rs3750847, rs3793917, and Surgical Oncology, Cancer rs1065489 were determined by matrix-assisted Institute and Hospital, Introduction laser desorption/ionization time-of-flight mass Chinese Academy of Medical Sciences, Peking – Age-related macular degeneration (AMD) is the spectrometry (MALDI-TOF-MS).
    [Show full text]
  • Genetic Susceptibility to Age-Related Macular Degeneration: a Paradigm for Dissecting Complex Disease Traits
    Human Molecular Genetics, 2007, Vol. 16, Review Issue 2 R174–R182 doi:10.1093/hmg/ddm212 Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits Anand Swaroop1,2,*, Kari EH Branham1, Wei Chen3 and Goncalo Abecasis3,* 1Departments of Ophthalmology and Visual Sciences, 2Department of Human Genetics and 3Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105, USA Received July 20, 2007; Revised July 20, 2007; Accepted July 26, 2007 Age-related macular degeneration (AMD) is a progressive neurodegenerative disease, which affects quality of life for millions of elderly individuals worldwide. AMD is associated with a diverse spectrum of clinical phe- notypes, all of which include the death of photoreceptors in the central part of the human retina (called the macula). Tremendous progress has been made in identifying genetic susceptibility variants for AMD. Variants at chromosome 1q32 (in the region of CFH ) and 10q26 (LOC387715/ARMS2) account for a large part of the genetic risk to AMD and have been validated in numerous studies. In addition, susceptibility var- iants at other loci, several as yet unidentified, make substantial cumulative contribution to genetic risk for AMD; among these, multiple studies support the role of variants in APOE and C2/BF genes. Genome-wide association and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal relationships that connect genetic variants to AMD pathogenesis and should assist in better design of prevention and intervention. INTRODUCTION studies of AMD illustrate both the promise and challenges of new gene-mapping approaches. Early-onset maculopathies, A vast majority of common diseases are complex and such as Stargardt’s disease, have long been known to have her- multi-factorial, resulting from the interplay of genetic com- editary basis.
    [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]
  • 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]
  • (12) United States Patent (10) Patent No.: US 7,972,787 B2 Deangelis (45) Date of Patent: Jul
    US007972 787B2 (12) United States Patent (10) Patent No.: US 7,972,787 B2 Deangelis (45) Date of Patent: Jul. 5, 2011 (54) METHODS FOR DETECTINGAGE-RELATED WO WO-2006088950 8, 2006 MACULAR DEGENERATION WO WO-2006133295 A2 12/2006 WO WO-2007044897 A1 4/2007 WO WO-2008O13893 A2 1, 2008 (75) Inventor: Margaret M. Deangelis, Cambridge, WO WO-2008067551 A2 6, 2008 MA (US) WO WO-2008094,370 A2 8, 2008 WO WO-2008103299 A2 8, 2008 WO WO-2008110828 A1 9, 2008 (73) Assignee: Massachusetts Eye and Ear Infirmary, WO WO-2008103299 A3 12/2008 Boston, MA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Hirschhornet al. Genetics in Medicine. Mar. 2002. vol. 4. No. 2, pp. patent is extended or adjusted under 35 45-61 U.S.C. 154(b) by 391 days. Yang et all. Science. 2006. 314: 992-993 and supplemental online content. (21) Appl. No.: 12/032,154 GeneCard for the HTRA1 gene available via url: <genecards.org/cgi bin/carddisp.pl?gene=Htral D, printed Jul. 20, 2010.* Lucentini et al. The Scientist (2004) vol. 18, p. 20.* (22) Filed: Feb. 15, 2008 Wacholder et al. J. Natl. Cancer Institute (2004) 96(6);434-442.* Ioannidis et al. Nature genetics (2001) 29:306-309.* (65) Prior Publication Data Halushka et al. Nature. Ju1 1999. 22: 239-247. “HtrA1: A novel TGFB antagonist.” Development (2003) 131:502. US 2008/O2O6263 A1 Aug. 28, 2008 Adams et al. “HTRA1 Genotypes Associated with Risk of Neovascular Age-related Macular Degeneration Independent of CFH Related U.S.
    [Show full text]
  • Population-Haplotype Models for Mapping and Tagging Structural Variation Using Whole Genome Sequencing
    Population-haplotype models for mapping and tagging structural variation using whole genome sequencing Eleni Loizidou Submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy Section of Genomics of Common Disease Department of Medicine Imperial College London, 2018 1 Declaration of originality I hereby declare that the thesis submitted for a Doctor of Philosophy degree is based on my own work. Proper referencing is given to the organisations/cohorts I collaborated with during the project. 2 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work 3 Abstract The scientific interest in copy number variation (CNV) is rapidly increasing, mainly due to the evidence of phenotypic effects and its contribution to disease susceptibility. Single nucleotide polymorphisms (SNPs) which are abundant in the human genome have been widely investigated in genome-wide association studies (GWAS). Despite the notable genomic effects both CNVs and SNPs have, the correlation between them has been relatively understudied. In the past decade, next generation sequencing (NGS) has been the leading high-throughput technology for investigating CNVs and offers mapping at a high-quality resolution. We created a map of NGS-defined CNVs tagged by SNPs using the 1000 Genomes Project phase 3 (1000G) sequencing data to examine patterns between the two types of variation in protein-coding genes.
    [Show full text]
  • A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy
    BRIEF COMMUNICATION www.jasn.org A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy †‡ Talat H. Malik,* Peter J. Lavin, Elena Goicoechea de Jorge,* Katherine A. Vernon,* | Kirsten L. Rose,* Mitali P. Patel,* Marcel de Leeuw,§ John J. Neary, Peter J. Conlon,¶ † Michelle P. Winn, and Matthew C. Pickering* *Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom; †Department of Medicine, Duke University Medical Center, Durham, North Carolina; ‡Trinity Health Kidney Centre, Tallaght Hospital, Trinity College, Dublin, Ireland; §Beckman Coulter Genomics, Grenoble, France; |Department of Renal Medicine, Royal Infirmary Edinburgh, Edinburgh, United Kingdom; and ¶Department of Nephrology, Beaumont Hospital, Dublin, Ireland ABSTRACT Controlled activation of the complement system, a key component of innate immunity, that CFHR1 and CFHR3 impair comple- enables destruction of pathogens with minimal damage to host tissue. Complement ment processing within the kidney. This factor H (CFH), which inhibits complement activation, and five CFH-related proteins hypothesis would predict that an increase (CFHR1–5) compose a family of structurally related molecules. Combined deletion of in CFHR1 and CFHR3 copy number would CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, enhance susceptibility to complement- we report an autosomal dominant complement-mediated GN associated with abnormal mediated kidney injury. Here, we report increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal a novel CFHR3–1 hybrid gene located on copies of these genes, affected individuals carry a unique hybrid CFHR3–1 gene. an allele that also contained intact copies In addition to identifying an association between these genetic observations and of the CFHR1 and CFHR3 genes.
    [Show full text]