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Caroline Klaver, Prof. dr.


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Caroline Klaver, Prof. dr.

Phone06-51934491
Emailc.c.w.klaver@erasmusmc.nl

Biographical Sketch

POSITION TITLE: Professor of Epidemiology and Genetics of Eye Disorders

 


EDUCATION/TRAINING

 

Institution and location Degree Completion Date Field of Study
Erasmus University Medical Center, Rotterdam, The Netherlands MD 1993 General Medicine
Erasmus University Medical Center, Rotterdam, The Netherlands MSc 1997 Clinical Epidemiology
Erasmus University Medical Center, Rotterdam, The Netherlands PhD 2000 Ophthalmology, Epidemiology
Erasmus University Medical Center, Rotterdam, The Netherlands Medical specialist 2001 Ophthalmology

 

Personal Statement

I am an ophthalmologist and a clinical epidemiologist specialized in ophthalmogenetics. My clinical expertise is in chronic retinal disorders, particularly AMD, in ophthalmogenetics, and in myopia. I was a member of the committee who developed the Preferred Practice Pattern for AMD (‘Richtlijn’), and helped to develop outcome measures in the international organization ICHOM. I became interested in patient management of myopia progression since 2011, as my genetic research on myopia was proceeding. I now treat progressive myopic children with atropine eye drops and/or orthokeratology (ortho-k), and have developed a tool for patient management as the frequency of side effects is high.

My research focuses on genetic-epidemiologic studies of various complex (myopia, age-related macular degeneration (AMD), glaucoma) and Mendelian eye disorders (retinal dystrophies). I am the principal investigator of ophthalmologic studies in 7 large epidemiologic cohorts from Rotterdam.

Gene finding: As a PhD student I was already focussed on gene finding, and I found one of the first genetic associations with AMD (i.e. APOE gene) using a candidate gene approach. During the last 5 years, my group has used genome-wide analysis high-throughput arrays to find associations with risk alleles. My group was the first to identify genes for common refractive error and myopia (Nat Genet 2010), for  glaucoma endophenotypes (Hum Mol Genet 2011), and for cone dystrophies (Am J Hum Genet 2009). When it became clear that bigger data sets were needed to reveal the entire genetic background, I became involved in international consortia. I set up the international consortium for refractive error and myopia (CREAM), which now includes 56 studies from Europe, US, Asia, and Australia with data from >60,000 participants. In CREAM, we found association with 26 genomic loci for refractive error (Nat Genet 2013); 9 loci for axial length (Am J Hum Genet. 2013); and 16 loci for corneal thickness (Nat Genet 2013). In parallel, my group participated in the glaucoma consortium (IGGC), AMD consortia (AMDGenomics; 3CC), and retinal dystrophy consortia (RP5000). The large data sets enabled gene finding for glaucoma (Nat Genet 2014; Nat Com 2014); for AMD (Nat Genet 2013); and for retinal dystrophies. For AMD, we are currently participating in large-scale exome analysis, while for the retinal dystrophies we are employing whole genome sequencing techniques.

Epidemiology and Genetic-epidemiology: I have been involved in classical epidemiologic studies since my PhD period, and in genetic epidemiology since 15 years. I have performed studies focussed at prevalence, incidence, risk factors, interaction, and prediction. My group investigated gene-environment interaction between environmental factors and the major gene (CFH gene) in AMD  (JAMA 2006). We recently expanded GxE studies with dietary intake (Arch Ophthalmol 2011; Ophthalmology 2014). Prediction modelling incorporating genetic as well as environmental factors for AMD started in 2007 (Arch Ophthalmol 2007), and we are  currently refining these models using pooled data from consortia (Ophthalmology 2013).

Functional studies: My experience with cell-based and animal studies started during my Master studies when I investigated HLA class II expression in mice. Later, I investigated apoE protein expression in human retinas after I identified the first association with the gene (Am J Hum Genet 1998), and recently I moved on to study functional consequences of myopia/glaucoma genes in zebrafish morpholino’s (Hum Mol Genet 2014). I obtained experience with genetic mouse models by examining ocular biometry in GJD2 knockout mice (Nat Genet 2010). Systems biology approaches is a new field of interest which I will be employing for AMD and myopia (Horizon2020 grant; VICI grant).

Positions and Honors

Positions

2001-2001:            Ophthalmologist in training, Erasmus MC, Rotterdam, The Netherlands

2001:                     Post-doctoral fellow, Genetics and Pathology, Iowas University, Iowa City, USA

2002:                     Post-doctoral fellow, Retina and Genetics, Columbia University & Vitreous-Retina-Macula Consultants, New York, USA

2003-onwards:      Ophthalmologist and senior researcher; Ophthalmology/Epidemiology, Erasmus MC, Rotterdam, The Netherlands

2003-2007:            Senior researcher, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

2007:                     Associate professor, Ophthalmology/Epidemiology; Erasmus MC, Rotterdam, The Netherlands

2011:                     Principle Investigator ophthalmology division Rotterdam Study

2012:                     Professor Ophthalmology/Epidemiology; Erasmus MC, Rotterdam, The Netherlands

2016:                     Ophthalmologist, Radboud UMC, Nijmegen (0.4 fte)

 

Honors 

1993:                     Medical Doctor degree with honors (cum laude)

2000:                     PhD degree with honors (cum laude)

2000:                     Erasmus University prize for best research

2000:                     Steven Hoogendijk Prize for best research Erasmus University and Technical University Delft

2001:                     Dutch government (NWO) Talent prize for research abroad

2002:                     Dutch Ophthalmic society for best research (NOG Donders prize)

2008:                     Dutch government (NWO) personal grant (VIDI)

2011:                     European Society of Ophthalmology (SOE) prize for significant career in Ophthalmology

2012:                     Bora prize for most innovative research (Bayer)

2014:                     European Union H2020 personal grant (ERC Consolidator)

2014:                     Dutch governement (NWO) personal grant (VICI)

2015:                     Royal Netherlands Academy of Arts and Sciences (KNAW) Ammodo Award – Biomedical Sciences

Contributions to Science

Total number of publications:             175

H-index: 42

 

Selected peer-reviewed publications:

  • Tideman JW, Polling JR, Voortman T, Jaddoe VW, Uitterlinden AG, Hofman A, Vingerling JR, Franco OH, Klaver CCW. Low serum vitamin D is associated with axial length and risk of myopia in young children. Eur J Epidemiol. 2016;31(5):491-9.
  • Polling JR, Kok RG, Tideman JW, Meskat B, Klaver CCW. Effectiveness study of atropine for progressive myopia in Europeans. Eye (Lond). 2016;30(7):998-1004.
  • Pierrache LH, Hartel BP, van Wijk E, Meester-Smoor MA, Cremers FP, de Baere E, de Zaeytijd J, van Schooneveld MJ, Cremers CW, Dagnelie G, Hoyng CB, Bergen AA, Leroy BP, Pennings RJ, van den Born LI, Klaver CCW. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. Ophthalmology. 2016;123(5):1151-60.
  • Delcourt C, Korobelnik JF, Buitendijk GH, Foster PJ, Hammond CJ, Piermarocchi S, Peto T, Jansonius N, Mirshahi A, Hogg RE, Bretillon L, Topouzis F, Deak G, Grauslund J, Broe R, Souied EH, Creuzot-Garcher C, Sahel J, Daien V, Lehtimaki T, Hense HW, Prokofyeva E, Oexle K, Rahi JS, Cumberland PM, Schmitz-Valckenberg S, Fauser S, Bertelsen G, Hoyng C, Bergen A, Silva R, Wolf S, Lotery A, Chakravarthy U, Fletcher A, Klaver CCW. Ophthalmic epidemiology in Europe: the "European Eye Epidemiology" (E3) consortium. Eur J Epidemiol. 2016;31(2):197-210.
  • Zhang L, Buitendijk GH, Lee K, Sonka M, Springelkamp H, Hofman A, Vingerling JR, Mullins RF, Klaver CCW, Abramoff MD. Validity of Automated Choroidal Segmentation in SS-OCT and SD-OCT. Invest Ophthalmol Vis Sci. 2015;56(5):3202-11.
  • Verhoeven VJ, Wong KT, Buitendijk GH, Hofman A, Vingerling JR, Klaver CCW. Visual consequences of refractive errors in the general population. Ophthalmology. 2015;122(1):101-9.
  • Wang JJ, Buitendijk GH, Rochtchina E, Lee KE, Klein BE, van Duijn CM, Flood VM, Meuer SM, Attia J, Myers C, Holliday EG, Tan AG, Smith WT, Iyengar SK, de Jong PT, Hofman A, Vingerling JR, Mitchell P, Klein R, Klaver CCW. Genetic susceptibility, dietary antioxidants, and long-term incidence of age-related macular degeneration in two populations. Ophthalmology. 2014;121(3):667-75.
  • Klein R, Myers CE, Buitendijk GH, Rochtchina E, Gao X, de Jong PT, Sivakumaran TA, Burlutsky G, McKean-Cowdin R, Hofman A, Iyengar SK, Lee KE, Stricker BH, Vingerling JR, Mitchell P, Klein BE, Klaver CCW, Wang JJ. Lipids, Lipid Genes and Incident Age-Related Macular Degeneration: The Three Continent Age-Related Macular Degeneration Consortium. Am J Ophthalmol. 2014.
  • Klein R, Meuer SM, Myers CE, Buitendijk GH, Rochtchina E, Choudhury F, de Jong PT, McKean-Cowdin R, Iyengar SK, Gao X, Lee KE, Vingerling JR, Mitchell P, Klaver CCW*, Wang JJ, Klein BE. Harmonizing the classification of age-related macular degeneration in the three-continent AMD consortium. Ophthalmic Epidemiol. 2014;21(1):14-23. Klaver CCW shared last author
  • Buitendijk GH, Amin N, Hofman A, van Duijn CM, Vingerling JR, Klaver CCW. Direct-to-Consumer Personal Genome Testing for Age-related Macular Degeneration. Invest Ophthalmol Vis Sci. 2014.
  • Verhoeven VJM, Buitendijk GHS, Rivadeneira F, Uitterlinden AG, Vingerling JR, Hofman A, Klaver CCW. Education influences the role of genetics in myopia. European Journal of Epidemiology. 2013;28(12):973-80.
  • Zhan X, Larson DE, Wang C, Koboldt DC, Sergeev YV, …., Klaver CCW, Pericak-Vance MA, Haines         JL, Weber BHF, Wilson RK, Heckenlively J, Chew EY, Stambolian D, Mardis ER, Swaroop A,    Abecasis GR. Identification of rare coding variants in complement 3 associated with age-related macular degeneration. Nat Genet. 2013;45:1375-9.
  • Verhoeven VJ, Hysi PG, Wojciechowski R, Fan Q, Guggenheim JA, Höhn R, Macgregor S, Hewitt AW,      …., Stambolian D, Klaver CCW*, Hammond CJ. Genome-wide meta-analyses of multiancestry cohorts       identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013;45:314-8. *Klaver CCW shared last, and corresponding author
  • Cheng CY, Schache M, Ikram MK, Young TL, Guggenheim JA, Vitart V, MacGregor S, Verhoeven VJM, …., Mackey DA, Klaver CCW*, Wong TY, Saw SM, Baird PN. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. Am J Hum Genet. 2013;93:264–277. *Klaver CCW shared last author
  • Thiadens AAHJ, Phan TM, Zekveld-Vroon RC, Leroy BP, van den Born LI, Hoyng CB, Klaver CCW. Clinical Course, Genetic Etiology, and Visual Outcome in Cone and Cone-Rod Dystrophy. Ophthalmology. 2012;119:819-26.
  • Hysi PG, Young TL, Mackey DA, Andrew T, Fernández-Medarde A, Solouki AM, Hewitt AW, Macgregor S, Vingerling JR, Li YJ, Ikram MK, Fai LY, Sham PC, Manyes L, Porteros A, Lopes MC, Carbonaro F, Fahy SJ, Martin NG, van Duijn CM, Spector TD, Rahi JS, Santos E, Klaver CCW, Hammond CJ. A    genome wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet. 2010;42:902-5.
  • Solouki AM, Verhoeven VJ, van Duijn CM, Verkerk AJ, Ikram MK, Hysi PG, Despriet DD, van Koolwijk LM, Ho L, Ramdas WD, Czudowska M, Kuijpers RW, Amin N, Struchalin M, Aulchenko YS, van Rij G, Riemslag FC, Young TL, Mackey DA, Spector TD, Gorgels TG, Willemse-Assink JJ, Isaacs A, Kramer       R, Swagemakers SM, Bergen AA, van Oosterhout AA, Oostra BA, Rivadeneira F, Uitterlinden AG, Hofman A, de Jong PT, Hammond CJ, Vingerling JR, Klaver CCW. A genome wide association study identifies a susceptibility locus for refractive error and myopia at 15q14. Nat Genet. 2010;42:897-901.
  • Ramdas WD, van Koolwijk LM, Ikram MK, Jansonius NM, de Jong PT, Bergen AA, Isaacs A, Amin N, Aulchenko YS, Wolfs RC, Hofman A, Rivadeneira F, Oostra BA, Uitterlinden AG, Hysi P, Hammond CJ, Lemij HG, Vingerling JR, Klaver CCW, van Duijn CM. A genome wide association study of optic disc parameters. PLoS Genet. 2010;6:e1000978.
  • Booij JC, Boon CJ, van Schooneveld MJ, ten Brink JB, Bakker A, de Jong PT, Hoyng CB, Bergen AA, Klaver CCW. Course of visual decline in relation to Best1 genotype in vitteliform macular dystrophy. Ophthalmology. 2010;117:1415-22.
  • Thiadens AAHJ, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere           E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CCW. Homozygosity mapping   reveals PDE6C mutations in patients with early-onset cone disorders. Am J Hum Genet 2009;85:240-7.
  • Klaver CCW, Bergen AAB. The SERPING1 gene and age-related macular degeneration. Lancet (editorial) 2008;372:1788-9.

Research Support

Total funding after obtaining PhD:      as Principal Investigator:                     €7,7 million

                                                            as Co-applicant:                                  €820 thousand

 

      s.r = success rate = proposals granted/all proposals

                      Grants applied for as Principal Investigator

Supplier

s.r

Title

Amount

Year

Uitzicht

23%

Diet recommendations for AMD

€94,000

2016

ERC-consolidator

10%

From genes to pathways: MYOP-PATH

€2,000,000

2015

NWO/VICI

10%

Towards solving myopia

€1,500,000

2015

Horizon2020

7%

Systems level analysis of AMD: EYE-RISK

€960,000

2015

KNAW

5%

Basic Ophthalmic research

€300,000

2015

Bright Focus

13%

Glaucoma Gene finding GIGA

€100,000

2015

Uitzicht

23%

AMD in Europe

€100,000

2015

Uitzicht

23%

Myopia pathogenesis into depth

€80,000

2014

CORR

20%

The GIGA project: glaucoma research in Africa

€101,000

2014

SNOO

 

prediction models of AMD

 €15,000

2013

SNOO

 

gene-environment interactions in myopia

 €15,000

2013

Uitzicht

30%

course of refractive error in Generation R

€125,000

2013

Uitzicht

30%

prediction models of AMD

€30,000

2013

Henkes

 

retinitis pigmentosa in RP5000 database

€15,000

2013

Uitzicht

30%

retinal imaging in Generation R

€85,000

2012

CORR

20%

genetic epidemiology of retinitis pigmentosa

€210,000

2012

Uitzicht

30%

NGS sequencing of 15q14 myopia locus

€92,000

2011

CORR

20%

GWAS of MYST Case-Control study

€180,000

2011

CORR

20%

founding of CORR-biobank for genetic eye diseases

€450,000

2010

Uitzicht

30%

genetic epidemiology of myopia

€100,000

2009

NWO/VIDI

15%

etiology of myopia

€600,000

2008

Low Vision org.

 

Cone disorders

€325,000

2006

Henkes

 

Cone disorders

€160,000

2004

S. v Essen Found.

 

AMD in ERF Study

€70,000

2003

EUR/Erasmus MC

 

EUR Fellowship grant; AMD in ERF Study

€100,000

2001

NWO

 

NWO Talent grant; fellowship abroad

€12,000

2001

 

 

Grants applied for as Co-Applicant

 

 

Uitzicht

23%

miRNA in AMD

€45,000

2015

Uitzicht

23%

The GIGA project: glaucoma research in Africa

€45,000

2015

Uitzicht

23%

Myopia families

€10,000

2015

Uitzicht

23%

The GIGA project: glaucoma research in Africa

€50,000

2014

Uitzicht

30%

RP5000 database and Stargardt disease

€110,000

2013

Uitzicht

30%

The Netherlands glaucoma study

€150,000

2012

Uitzicht

30%

retinal dystr. in The Netherlands.; RP5000 datab.

€125,500

2011

Uitzicht

30%

retinal imaging in Rotterdam Study

€150,000

2010

Uitzicht

30%

molecular studies on cone dysfunction disorders

€135,000

2009

 

 
 
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