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First genome-wide association (GWAS) study on the systemic complement activation system identifies markers potentially significant for treatment of AMD

Researchers based at the Department of Ophthalmology at Radboud University Medical Center, Nijmegen, the Netherlands, have shown that variants of the  CFH and CFHR4 genes are associated with variation in the systemic complement activation system, and thereby potentially relevant to how certain AMD patients may respond to therapeutics based on complement biology.  The research, conducted on participants with and without AMD, uncovered two markers which associate with higher activation of the complement system, potentially explaining up to 18.7% of the variability observed.  The findings may contribute to the stratification of patients most likely to respond to complement-based therapeutics.


Genome-wide association studies represent a powerful research tool that examine millions of genetic variations, or “SNPs”, within a large population of participants to determine how such genetic variation might associate with clinical variation, and thereby uncover potential genetic causes, or contributing genetic factors, that lead to specific disease.  The technology originally presented the promise of a powerful tool to find the needle (gene) in the haystack (genome), but as time has shown, GWAS has revealed how complex biology can be.  Rarely does a single gene cause a single disorder so researchers often end-up finding several needles in a stack of needles.  Nevertheless, the technology has uncovered the detail and richness that exists between genotype and phenotype, and provides a far deeper and more fundamental understanding of the disease process across multiple fields of medicine.  In the current study, researchers in Nijmegen, carried out a GWAS on, 2,245 subjects in parallel to collecting their AMD status and other basic clinical information.


As is well documented in the medical literature, the complement system is a fundamental part of innate immunity involved in host defence and homeostasis and may be activated in a variety of ways, with the “alternative pathway”, or “AP”, being of particular relevance to AMD pathology. Dysregulation of this alternative pathway has been linked to AMD, no less so than through several genetic studies showing that variants of complement genes may increase or decrease susceptibility to the disorder.  Research has shown that there is considerable variation in the level of systemic complement activation in humans and so patients with higher levels of activation may benefit more from complement-based therapies compared to patients with lower levels of activation.  In order to identify such potential positive “responders”, the Dutch research team conducted an hypothesis-free study to examine what genetic signals might associate with systemic activation of the complement system.  The research identified two variants, “rs3753396” (c.2016A/ G, p.Gln672Gln) in the coding region of the CFH  gene, and “rs6685931” (c.59e 4315T/ C), in the non-coding region of the CFHR4 gene.  While both markers were found to have a significant effect on systemic activation of the complement system, the second marker (rs6685931) may have a higher risk association with AMD, and may therefore be used to identify potential patients that might benefit from complement-based therapy.  While the study provides some tantalizing pointers for future lines of research, a larger study may have the power to tease out potential causal relationships, furthering the ability of researchers to optimize patient stratification for clinical research, while additionally pinpointing future potential therapeutic targets.