June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Towards precision medicine in AMD: Genome-wide association study reveals genetic variants in CFH and CFHR4 that are strongly associated with complement activation levels
Author Affiliations & Notes
  • Laura Lorés de Motta
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Constantin Paun
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Jordi Corominas
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Department of Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Maartje Geerlings
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Lebriz Altay
    Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
  • Tina Schick
    Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
  • Bjorn Bakker
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Joannes Groenewoud
    Department for Health and Evidence, Radboud university medical center, Nijmegen, Netherlands
  • Mohamed Daha
    Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
  • Sascha Fauser
    Ophthalmology, Roche, Basel, Switzerland
    Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
  • Anneke I Den Hollander
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Department of Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Eiko de Jong
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   Laura Lorés de Motta, None; Constantin Paun, None; Jordi Corominas, None; Maartje Geerlings, None; Lebriz Altay, None; Tina Schick, Bayer Health Care (R); Bjorn Bakker, None; Joannes Groenewoud, None; Mohamed Daha, None; Sascha Fauser, Roche (E); Anneke Den Hollander, None; Eiko de Jong, None
  • Footnotes
    Support  The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 310644 (MACULA).
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 809. doi:
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      Laura Lorés de Motta, Constantin Paun, Jordi Corominas, Maartje Geerlings, Lebriz Altay, Tina Schick, Bjorn Bakker, Joannes Groenewoud, Mohamed Daha, Sascha Fauser, Anneke I Den Hollander, Eiko de Jong; Towards precision medicine in AMD: Genome-wide association study reveals genetic variants in CFH and CFHR4 that are strongly associated with complement activation levels. Invest. Ophthalmol. Vis. Sci. 2017;58(8):809.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Several lines of evidence point towards an over-activation of the complement system in age-related macular degeneration (AMD). Consequently, new therapies are being developed that aim to inhibit complement activity. Most likely, patients with the highest levels of complement activation will benefit most from such therapies. Therefore, the purpose of this study was to identify genetic variants associated with complement activation, which could help to select patients for complement inhibition therapies.

Methods : A genome-wide association study on serum C3d/C3 levels was performed in 1548 AMD patients and controls. Linear regression analysis of ln(C3d/C3) was conducted adjusting for age, sex, body mass index, triglyceride levels, AMD status and the first two ancestry principal components. After imputation and quality control procedures, 9,972,920 variants were included in the analysis. For replication and meta-analysis, 697 additional individuals were genotyped for rs3753396 and rs6685931. FH serum levels were measured in 350 of the study participants using ELISA. Haplotype analysis was performed for eight SNPs across the CFH/CFHR locus.

Results : Complement activation levels were independently associated with rs3753396 located in the CFH gene (p-value discovery=1.10x10-15 meta=3.66x10-21, β=0.141, SE=0.015) and rs6685931 located in the CFHR4 gene (p-value discovery=8.18x10-7 meta=6.32x10-8, β=0.054, SE=0.010). Moreover, rs3753396 in CFH was associated with lower FH levels (p-value=1,33x10-4, β(AG)=-24.55, SE=6.36 µg/ml). Haplotype analysis revealed several common haplotypes with stronger effects on complement activation compared to the single variant analysis. In addition, a rare haplotype (frequency 0.4%) not carrying any of the previously identified common risk variants, showed a strong effect on complement activation (p-value=0.001, β=0.405, SE=0.129).

Conclusions : Common genetic variation in CFH and CFHR4 is associated with variability in complement activation, possibly through alteration of FH levels. Moreover, a rare haplotype in the CFH/CFHR locus was identified, which might carry a rare genetic variant with a strong effect on complement activation. Genotypes are robust markers and, therefore, the results of this study may be used to select AMD patients that would benefit most from complement inhibition therapies.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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