Sub theme 2.7
Diagnosis and treatment of disorders of the posterior segment and strabismus

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

Overall aim

The aim of my research is to unravel the hereditary retinal disorders, to create insight into the pathogenic pathways underlying these traits, and to develop strategies for early identification of high-risk individuals.

Key objectives

  1. To identify genetic and environmental risk factors for hereditary retinal disorders, and assess the contribution of these factors to the overall disease occurrence.
  2. To study gene-gene and gene-environment interactions, and specifically investigate whether the effect of genetic susceptibility alleles is triggered by environmental factors.
  3. To evaluate whether genetic testing can be used to predict progression of hereditary retinal disorders and its clinical complications, and develop strategies for early identification of groups at high risk of severe visual loss.

Scientific achievements

My initial and most prominent research comprised epidemiology, genetic-epidemiology, and genetics of age-related macular degeneration (AMD), the leading cause of blindness among the elderly. During my PhD training, I had executed family studies within the population-based Rotterdam Study (Paulus de Jong, Bert Hofman), and discovered that AMD was strongly genetically determined.

After my doctorate, I set up an ophthalmologic study involving the genetic etiology of AMD, glaucoma, and myopia, a study which was embedded in a large investigation of a genetic isolate executed by Erasmus MC (Cornelia van Duijn, Ben Oostra). During 1.3 yrs as a post-doc in the USA, I assessed skills in molecular genetics, and was involved in 2 large case-control studies investigating the genetic causes of AMD. This resulted in a long-term international collaboration which formed the basis for the discovery of the Complement factor H (CFH) gene as a major gene for AMD. After my return to the Netherlands, I attracted two PhD students to continue the work in the genetic isolate study, but also took part in a clinic-based case-control study in which I supervised the screening of candidate genes. To verify findings of prominent AMD genes, and to increase statistical power for more complex analyses, we formed a collaboration between the Rotterdam Study, the case-control study, and the genetic isolate study. This pooled data set proved to be very fruitful, and led to the discovery of interaction between smoking, inflammatory markers and the CFH gene, to discovery of interactions between the CFH-CRP genes, and the CFH-LOC genes, and to assessment of the predictive value of multiple genetic testing for AMD.

My interest has recently switched to myopia. This started when I was evaluating the causes of blindness in the Netherlands and discovered that this was the most important cause of legal blindness at middle-age. In a later project, we assessed the genetic risk of retinal detachment and found that the major reason for familial aggregation was the high familial occurrence of myopia. This was a stimulus to implement the assessment of myopia parameters in the epidemiologic studies mentioned above, and created the scientific drive for a new project.

Future plans: special goals and approach

An important new research project is the study on etiologic factors for myopia. Myopia, or nearsightedness, is a common ocular disorder which is highly heritable, and which may lead to blindness. There are currently no treatment options available to halt progression of myopia, or to cure the vision-disabling complications. Findings from animal studies have not revealed potential causes of the disease in humans. A widely accepted view is that multiple genetic and environmental risk factors underlie the pathogenesis, but no factors have been identified to date. The polygenic inheritance of genes with minor effects and the phenotypic complexity have posed a major challenge for research.

We propose to employ four large, well-designed epidemiologic settings to assess environmental and genetic risk factors: a population-based study of middle-aged and elderly subjects, a study in a genetic isolate, a clinic-based case-control study, and a population-based study in children. These studies all have information on various personal, medical, and life style factors, and have extensive data from different disease areas, including ocular parameters as refractive error, axial length, and photographs of the retina. We will exploit the recent technological advances to rapidly scan genetic markers across the genome, and use genome wide association analysis to identify causal genes. The different study populations will facilitate validation of findings, enable quantification of the population-attributable risk, and provide possibilities to study influence of genetic factors on onset of myopia in childhood as well as on the complications later in life.

Once genetic factors are identified, we will further study gene-environment interaction, and particularly investigate whether factors as many hours of reading at an early age can act as a trigger for onset of myopia when the genetic risk is high. We will explore whether genetic factors can be used to predict progression of myopia, and develop a prediction model to identify high-risk individuals. The ultimate goal of this study is to develop better strategiesto detect, treat, and prevent progression and complications from myopia.

Most recent publications
  1. Klaver CCW, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PTVM. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet. 1998;63:200-6.
  2. Klaver CCW, Assink JJM, Bergen AAB, van Duijn CM. ABCR and age-related macular degeneration. Science 1998;279:1107.
  3. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CCW, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci 2005;102:7227-32.
  4. van Leeuwen R, Boekhoorn S, Vingerling JR, Witteman JC, Klaver CCW, Hofman A, de Jong PTVM. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005; 294:3101-7.
  5. Despriet DDG, Klaver CCW, Witteman JCM, Bergen AAB, Kardys I, de Maat MPM, Boekhoorn SS, Vingerling JR, Hofman A, Oostra BA, Uitterlinden AG, Stijnen T, van Duijn CM, de Jong PTVM. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006;296:301-309.
  6. Jager MJ, Klaver CCW. Macrophages feel their age in macular degeneration. Editorial. J. Clin Invest. 2007;117:3182-3184.
  7. Klaver CCW, Bergen AA. The SERPING1 gene and age-related macular degeneration. Lancet. 2008 Nov 22;372(9652):1788-9.
  8. DDG Despriet, CM van Duijn, BA Oostra, AG Uitterlinden, A. Hofman, AF Wright, JB ten Brink, A Bakker,  PTVM de Jong, JR Vingerling, AAB Bergen, CCW Klaver. Complement component C3 and risk of age-related macular degeneration. Ophthalmology 2009; 116:474-480.
  9. Allikmets R, Bergen AA, Dean M, Guymer RH, Hageman GS, Klaver CCW, Stefansson K, Weber BH; International Age-related Macular Degeneration Genetics Consortium. Geographic atrophy in age-related macular degeneration and TLR3. N Engl J Med. 2009;360:2252-4.
  10. Thiadens AA, 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 photoreceptor disorders. Am J Hum Genet. 2009;85:240-7.