Abstract
BackgroundSingle-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus).ResultsBy refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes.ConclusionsOur study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.
Highlights
Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively
Haplotypes based on complement factor H (CFH) I62V, CFHR3/1 deletion and CFH Y402H differentiate disease susceptibility at the CFH‐CFHR5 locus The risk allele (T) for the International AMD Genetic Consortium (IAMDGC) Locus 1.5, which was independently associated with increased risk for AMD in a previous Genome-wide association studies (GWAS) [34], exists exclusively on a low-frequency haplotype containing a C allele at rs1061170
When considering the effect size associated with combinations of risk, neutral and protective haplotypes on Chr1 and risk alleles on Chr10, we find that, as expected for additive genetic contributions, age-related maculopathy susceptibility 2 (ARMS2)/high-temperature requirement factor A1 (HTRA1) risk alleles are counteracted by protective CFH-CFHR5 haplotypes in an approximately one-to-one manner
Summary
Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the USA [1, 2] and affects close to 200 million individuals worldwide [3]. A fraction of patients [3] progress to the late form of the disease, which is characterized by the gradual atrophy of regions of the retina (geographic atrophy, GA) and/or the abnormal growth of choroidal and/or retinal vessels (neovascular AMD) [15]. Therapeutic options are currently limited to patients with neovascular AMD, these therapies suffer from inconsistent clinical outcomes [16,17,18,19,20,21]
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