Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration.

Aged Apolipoproteins / blood Capillaries / metabolism Case-Control Studies Complement Activation Complement Factor H / metabolism Genetic Predisposition to Disease Genome-Wide Association Study Haplotypes Humans Intracellular Signaling Peptides and Proteins / metabolism LIM Domain Proteins / metabolism Liver / physiology Macular Degeneration / blood Muscle Proteins / metabolism Polymorphism, Single Nucleotide Retina / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
07 02 2020
Historique:
received: 15 03 2019
accepted: 10 01 2020
entrez: 9 2 2020
pubmed: 9 2 2020
medline: 19 5 2020
Statut: epublish

Résumé

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10

Identifiants

DOI: 10.1038/s41467-020-14499-3 PMID: 32034129 PMC: PMC7005798
pubmed: 32034129
doi: 10.1038/s41467-020-14499-3
pii: 10.1038/s41467-020-14499-3
pmc: PMC7005798
doi:

Substances chimiques

Apolipoproteins 0
CFH protein, human 0
CFHR4 protein, human 0
FHL1 protein, human 0
Intracellular Signaling Peptides and Proteins 0
LIM Domain Proteins 0
Muscle Proteins 0
Complement Factor H 80295-65-4

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

778

Subventions

Organisme : NEI NIH HHS
ID : R01 EY022310
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008C
Pays : United States
Organisme : Medical Research Council
ID : MR/P025838/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K024418/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States

Références

Wong, W. L. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2, e106–e116 (2014).
pubmed: 25104651 doi: 10.1016/S2214-109X(13)70145-1 pmcid: 25104651
Curcio, C. A. Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies. Invest. Ophthalmol. Vis. Sci. 59, AMD160–AMD181 (2018).
pubmed: 30357336 pmcid: 6733535 doi: 10.1167/iovs.18-24882
Crabb, J. W. The proteomics of drusen. Cold Spring Harb. Perspect. Med. 4, a017194 (2014).
pubmed: 24799364 pmcid: 4066642 doi: 10.1101/cshperspect.a017194
Ferris, F. L. 3rd et al. Clinical classification of age-related macular degeneration. Ophthalmology 120, 844–851 (2013).
pubmed: 23332590 doi: 10.1016/j.ophtha.2012.10.036
Fritsche, L. G. et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat. Genet. 48, 134–143 (2016).
pubmed: 26691988 doi: 10.1038/ng.3448
McHarg, S., Clark, S. J., Day, A. J. & Bishop, P. N. Age-related macular degeneration and the role of the complement system. Mol. Immunol. 67, 43–50 (2015).
pubmed: 25804937 doi: 10.1016/j.molimm.2015.02.032
Schramm, E. C. et al. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol. Immunol. 61, 118–125 (2014).
pubmed: 25034031 pmcid: 4149817 doi: 10.1016/j.molimm.2014.06.032
Edwards, A. O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).
pubmed: 15761121 doi: 10.1126/science.1110189
Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl Acad. Sci. USA 102, 7227–7232 (2005).
pubmed: 15870199 doi: 10.1073/pnas.0501536102
Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).
pubmed: 15761120 doi: 10.1126/science.1110359
Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
pubmed: 15761122 pmcid: 1512523 doi: 10.1126/science.1109557
Raychaudhuri, S. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 43, 1232–1236 (2011).
pubmed: 22019782 pmcid: 3225644 doi: 10.1038/ng.976
Fontaine, M. et al. Truncated forms of human complement factor H. Biochem. J. 258, 927–930 (1989).
pubmed: 2525027 pmcid: 1138455 doi: 10.1042/bj2580927
Ripoche, J., Day, A. J., Harris, T. J. & Sim, R. B. The complete amino acid sequence of human complement factor H. Biochem. J. 249, 593–602 (1988).
pubmed: 2963625 pmcid: 1148743 doi: 10.1042/bj2490593
Clark, S. J. et al. Identification of factor H-like protein 1 as the predominant complement regulator in bruch's membrane: implications for age-related macular degeneration. J. Immunol. 193, 4962–4970 (2014).
pubmed: 25305316 pmcid: 4225158 doi: 10.4049/jimmunol.1401613
de Jorge, E. G. et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc. Natl Acad. Sci. USA 110, 4685–4690 (2013).
doi: 10.1073/pnas.1219260110
Clark, S. J. & Bishop, P. N. Role of factor H and related proteins in regulating complement activation in the macula, and relevance to age-related macular degeneration. J. Clin. Med. 4, 18–31 (2015).
pubmed: 25729613 doi: 10.3390/jcm4010018
Triebwasser, M. P. et al. Rare variants in the functional domains of complement factor H are associated with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 56, 6873–6878 (2015).
pubmed: 26501415 pmcid: 4627248 doi: 10.1167/iovs.15-17432
Geerlings, M. J. et al. The functional effect of rare variants in complement genes on C3b degradation in patients with age-related macular degeneration. JAMA Ophthalmol. 135, 39–46 (2017).
pubmed: 27918759 doi: 10.1001/jamaophthalmol.2016.4604
Hoffman, J. D. et al. Rare complement factor H variant associated with age-related macular degeneration in the Amish. Invest. Ophthalmol. Vis. Sci. 55, 4455–4460 (2014).
pubmed: 24906858 pmcid: 4107619 doi: 10.1167/iovs.13-13684
Yu, Y. et al. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum. Mol. Genet. 23, 5283–5293 (2014).
pubmed: 24847005 pmcid: 4159152 doi: 10.1093/hmg/ddu226
Geerlings, M. J., de Jong, E. K. & den Hollander, A. I. The complement system in age-related macular degeneration: a review of rare genetic variants and implications for personalized treatment. Mol. Immunol. 84, 65–76 (2017).
pubmed: 27939104 pmcid: 5380947 doi: 10.1016/j.molimm.2016.11.016
Calippe, B. et al. Complement factor H inhibits CD47-mediated resolution of inflammation. Immunity 46, 261–272 (2017).
pubmed: 28228282 doi: 10.1016/j.immuni.2017.01.006
Laine, M. et al. Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J. Immunol. 178, 3831–3836 (2007).
pubmed: 17339482 pmcid: 4853917 doi: 10.4049/jimmunol.178.6.3831
Weismann, D. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478, 76–81 (2011).
pubmed: 21979047 pmcid: 4826616 doi: 10.1038/nature10449
Clark, S. J. et al. Impaired binding of the Amd-associated complement factor H 402h allotype to Bruch’s membrane in human retina. Invest. Ophthalmol. Vis. Sci. 51, 400 (2010).
Fritsche, L. G. et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum. Mol. Genet. 19, 4694–4704 (2010).
pubmed: 20843825 doi: 10.1093/hmg/ddq399
Hageman, G. S. et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann. Med. 38, 592–604 (2006).
pubmed: 17438673 pmcid: 1905836 doi: 10.1080/07853890601097030
Hughes, A. E. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat. Genet. 38, 1173–1177 (2006).
pubmed: 16998489 doi: 10.1038/ng1890
Raychaudhuri, S. et al. Associations of CFHR1–CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat. Genet. 42, 553 (2010).
pubmed: 20581873 pmcid: 3138072 doi: 10.1038/ng0710-553
Spencer, K. L. et al. Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration. Hum. Mol. Genet. 17, 971–977 (2008).
pubmed: 18084039 doi: 10.1093/hmg/ddm369 pmcid: 18084039
Kubista, K. E. et al. Copy number variation in the complement factor H-related genes and age-related macular degeneration. Mol. Vis. 17, 2080–2092 (2011).
pubmed: 21850184 pmcid: 3156785
Cantsilieris, S. et al. Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family. Proc. Natl Acad. Sci. USA 115, E4433–E4442 (2018).
pubmed: 29686068 doi: 10.1073/pnas.1717600115 pmcid: 29686068
Sivakumaran, T. A. et al. A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration. PLos ONE 6, e25598 (2011).
pubmed: 22022419 pmcid: 3192039 doi: 10.1371/journal.pone.0025598
Chirco, K. R. et al. Evaluation of serum and ocular levels of membrane attack complex and C-reactive protein in CFH-genotyped human donors. Eye 32, 1740–1742 (2018).
pubmed: 30013157 pmcid: 6224589 doi: 10.1038/s41433-018-0170-8
Keenan, T. D. L. et al. Assessment of proteins associated with complement activation and inflammation in maculae of human donors homozygous risk at chromosome 1 CFH-to-F13B. Invest. Ophthalmol. Vis. Sci. 56, 4870–4879 (2015).
pubmed: 26218915 doi: 10.1167/iovs.15-17009 pmcid: 26218915
Mullins, R. F. et al. The membrane attack complex in aging human choriocapillaris relationship to macular degeneration and choroidal thinning. Am. J. Pathol. 184, 3142–3153 (2014).
pubmed: 25204844 pmcid: 4215023 doi: 10.1016/j.ajpath.2014.07.017
Whitmore, S. S. et al. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy. Prog. Retin Eye Res. 45, 1–29 (2015).
pubmed: 25486088 doi: 10.1016/j.preteyeres.2014.11.005 pmcid: 25486088
Lores-Motta, L. et al. Genome-wide association study reveals variants in CFH and CFHR4 associated with systemic complement activation: implications in age-related macular degeneration. Ophthalmology 125, 1064–1074 (2018).
pubmed: 29398083 doi: 10.1016/j.ophtha.2017.12.023 pmcid: 29398083
Strunz, T., et al. A mega-analysis of expression quantitative trait loci (eQTL) provides insight into the regulatory architecture of gene expression variation in liver. Sci Rep 8, 5865 (2018).
Strunnikova, N. V. et al. Transcriptome analysis and molecular signature of human retinal pigment epithelium. Hum. Mol. Genet. 19, 2468–2486 (2010).
pubmed: 20360305 pmcid: 2876890 doi: 10.1093/hmg/ddq129
Wagner, A. H. et al. Exon-level expression profiling of ocular tissues. Exp. Eye Res. 111, 105–111 (2013).
pubmed: 23500522 doi: 10.1016/j.exer.2013.03.004
Whitmore, S. S. et al. Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells. Mol. Vis. 19, 2274–2297 (2013).
pubmed: 24265543 pmcid: 3834599
Li, M. Y. et al. Comprehensive analysis of gene expression in human retina and supporting tissues. Hum. Mol. Genet. 23, 4001–4014 (2014).
pubmed: 24634144 doi: 10.1093/hmg/ddu114
Kim, E. J. et al. Complete transcriptome profiling of normal and age-related macular degeneration eye tissues reveals dysregulation of anti-sense transcription. Sci. Rep. 8, 3040 (2018).
pubmed: 29445097 pmcid: 5813239 doi: 10.1038/s41598-018-21104-7
GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
doi: 10.1126/science.1262110
Hebecker, M. & Józsi, M. Factor H-related protein 4 activates complement by serving as a platform for the assembly of alternative pathway C3 convertase via its interaction with C3b protein. J. Biol. Chem. 287, 19528–19536 (2012).
pubmed: 22518841 pmcid: 3365989 doi: 10.1074/jbc.M112.364471
Hellwage, J. et al. Functional properties of complement factor H-related proteins FHR-3 and FHR-4: binding to the C3d region of C3b and differential regulation by heparin. FEBS Lett. 462, 345–352 (1999).
pubmed: 10622723 doi: 10.1016/S0014-5793(99)01554-9
Clark, S. J. & Bishop, P. N. The eye as a complement dysregulation hotspot. Semin. Immunol. 40, 65–74 (2018).
doi: 10.1007/s00281-017-0649-6
Kunchithapautham, K., Atkinson, C. & Rohrer, B. Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation. J. Biol. Chem. 289, 14534–14546 (2014).
pubmed: 24711457 pmcid: 4031511 doi: 10.1074/jbc.M114.564674
Toomey, C. B., Kelly, U., Saban, D. R. & Rickman, C. B. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc. Natl Acad. Sci. USA 112, E3040–E3049 (2015).
pubmed: 25991857 doi: 10.1073/pnas.1424391112
Ansari, M. et al. Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration. Hum. Mol. Gene.t 22, 4857–4869 (2013).
doi: 10.1093/hmg/ddt336
Guymer, R. et al. Plasma levels of amyloid beta and other proinflammatory mediators in patients with age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 253, 1347–1354 (2015).
pubmed: 25744331 doi: 10.1007/s00417-015-2970-x
Hakobyan, S. et al. Measurement of factor H variants in plasma using variant-specific monoclonal antibodies: application to assessing risk of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 49, 1983–1990 (2008).
pubmed: 18436830 doi: 10.1167/iovs.07-1523
Reynolds, R. et al. Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest. Ophthalmol. Vis. Sci. 50, 5818–5827 (2009).
pubmed: 19661236 pmcid: 2826794 doi: 10.1167/iovs.09-3928
Scholl, H. P. N. et al. Systemic complement activation in age-related macular degeneration. PLoS ONE 3, e2593 (2008).
pubmed: 18596911 pmcid: 2440421 doi: 10.1371/journal.pone.0002593
Sharma, N. K. et al. Association between CFH Y402H polymorphism and age related macular degeneration in North Indian Cohort. PLoS ONE 8, e70193 (2013).
pubmed: 23922956 pmcid: 3726372 doi: 10.1371/journal.pone.0070193
Sharma, N. K. et al. Predictive model for earlier diagnosis of suspected age-related macular degeneration patients. DNA Cell Biol. 32, 549–555 (2013).
pubmed: 23848218 doi: 10.1089/dna.2013.2072
Silva, A. S. et al. Plasma levels of complement proteins from the alternative pathway in patients with age-related macular degeneration are independent of complement factor H Tyr
pubmed: 22969267 pmcid: 3436886
Smailhodzic, D. et al. Risk alleles in CFH and ARMS2 are independently associated with systemic complement activation in age-related macular degeneration. Ophthalmology 119, 339–346 (2012).
pubmed: 22133792 doi: 10.1016/j.ophtha.2011.07.056
Clark, S. J., McHarg, S., Tilakaratna, V., Brace, N. & Bishop, P. N. Bruch’s membrane compartmentalizes complement regulation in the eye with implications for therapeutic design in age-related macular degeneration. Front. Immunol. 8, 1778 (2017).
Taylor, R. L., et al. Loss-of-function mutations in the CFH gene affecting alternatively encoded factor H-like 1 protein cause dominant early-onset macular drusen. Ophthalmology https://doi.org/10.1016/j.ophtha.2019.03.013 (2019).
pubmed: 30905644 pmcid: 6856713 doi: 10.1016/j.ophtha.2019.03.013
Wagner, E. K. et al. Mapping rare, deleterious mutations in Factor H: association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci. Rep. 6, 31531 (2016).
pubmed: 27572114 pmcid: 5004131 doi: 10.1038/srep31531
Kavanagh, D. et al. Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Hum. Mol. Genet. 24, 3861–3870 (2015).
pubmed: 25788521 pmcid: 4459386
Yates, J. R. W. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 357, 553–561 (2007).
pubmed: 17634448 doi: 10.1056/NEJMoa072618
Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).
pubmed: 23128226 doi: 10.1038/nature11632
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
pubmed: 11315092 doi: 10.1111/j.0006-341X.1999.00997.x
Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
pubmed: 20616382 pmcid: 2922887 doi: 10.1093/bioinformatics/btq340
Pruim, R. J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
pubmed: 20634204 pmcid: 2935401 doi: 10.1093/bioinformatics/btq419

Auteurs

Valentina Cipriani (V)

William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, EC1M 6BQ, UK. v.cipriani@qmul.ac.uk.
UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK. v.cipriani@qmul.ac.uk.
Moorfields Eye Hospital NHS Foundation Trust, London, EC1V 2PD, UK. v.cipriani@qmul.ac.uk.
UCL Genetics Institute, University College London, London, WC1E 6BT, UK. v.cipriani@qmul.ac.uk.
ORCID: 0000-0002-0839-9955

Laura Lorés-Motta (L)

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.

Fan He (F)

Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
ORCID: 0000-0003-2651-6518

Dina Fathalla (D)

Systems Immunity URI, Division of Infection and Immunity, and UK DRI Cardiff, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
ORCID: 0000-0003-3845-529X

Viranga Tilakaratna (V)

Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.

Selina McHarg (S)

Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.

Nadhim Bayatti (N)

Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.

İlhan E Acar (İE)

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
ORCID: 0000-0002-2078-9905

Carel B Hoyng (CB)

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.

Sascha Fauser (S)

Department of Ophthalmology, University Hospital of Cologne, Cologne, 50924, Germany.
Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland.

Anthony T Moore (AT)

UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
Moorfields Eye Hospital NHS Foundation Trust, London, EC1V 2PD, UK.
Ophthalmology Department, University of California San Francisco, San Francisco, CA, USA.

John R W Yates (JRW)

UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
Moorfields Eye Hospital NHS Foundation Trust, London, EC1V 2PD, UK.
Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.

Eiko K de Jong (EK)

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
ORCID: 0000-0001-6520-0407

B Paul Morgan (BP)

Systems Immunity URI, Division of Infection and Immunity, and UK DRI Cardiff, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.

Anneke I den Hollander (AI)

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, 6525 HR, The Netherlands.
ORCID: 0000-0003-0634-5408

Paul N Bishop (PN)

Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.

Simon J Clark (SJ)

Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. simon.clark@uni-tuebingen.de.
The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. simon.clark@uni-tuebingen.de.
Department of Ophthalmology, Research Institute of Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany. simon.clark@uni-tuebingen.de.
ORCID: 0000-0001-8394-8355

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Increased circulating levels of Factor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Increased circulating levels of Factor...
questionsmedicales.fr › Système cardiovasculaire › Vaisseaux sanguins › Microvaisseaux › Vaisseaux capillaires › Increased circulating levels of Factor...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Increased circulating levels of Factor...
questionsmedicales.fr › Phénomènes du système immunitaire › Activation du complément › Increased circulating levels of Factor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › bêta-Globulines › Facteur H du complément › Increased circulating levels of Factor...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Increased circulating levels of Factor...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Increased circulating levels of Factor...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Haplotypes › Increased circulating levels of Factor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Increased circulating levels of Factor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Increased circulating levels of Factor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines à domaine LIM › Increased circulating levels of Factor...
questionsmedicales.fr › Système digestif › Foie › Increased circulating levels of Factor...
questionsmedicales.fr › Maladies de l'oeil › Rétinopathies › Dégénérescence de la rétine › Dégénérescence maculaire › Increased circulating levels of Factor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines contractiles › Protéines du muscle › Increased circulating levels of Factor...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Increased circulating levels of Factor...
questionsmedicales.fr › Organes des sens › Oeil › Rétine › Increased circulating levels of Factor...