Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10−6), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10−56), independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.
Highlights
Age-related macular degeneration (AMD) is a leading cause of blindness
FHR-4 likely predisposes to disease by penetrating the extracellular matrix (ECM) of the choriocapillaris and Bruch’s membrane (BrM) and acting locally by facilitating complement activation
FHlike 1 (FHL-1) is the complement regulator primarily responsible for protecting intercapillary septa ECM from complement activation[6,15], but this protective function may be inhibited by FHR-4
Summary
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Soft drusen are an early sign of AMD These deposits form within Bruch’s membrane (BrM) underneath the retinal pigment epithelium (RPE) basement membrane and contain apolipoprotein B and E, cholesterol-rich lipoproteins that are thought to be derived from the RPE2. AMD has a strong genetic basis; associations with 45 common single-nucleotide polymorphisms (SNPs) and 7 rare variants across 34 genetic loci have been reported in the largest genomewide association study (GWAS) to date, explaining ~34% of AMD risk[5] Many of these variants reside in genes encoding complement system components, those encoded at the regulators of complement activation (RCA) locus on chromosome 1q31.3, including factor H (FH; CFH) and FH-related 1–5 (CFHR1–5)[6,7].
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