CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD

Abstract

BackgroundAge-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear.Methods and FindingsWe genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10−12) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10−9) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD).ConclusionSoft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.

HTRA1, an age‐related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

“…Thus, if the CFH Y402H risk mutation lowers its affinity for CRP, then the lack of inhibition might be expected to trigger overactive inflammation in the extracellular space. The CFH risk allele is associated with increased soft drusen in the eye, and immunohistochemical and proteomic studies of drusen composition revealed several complement proteins in addition to CFH (Crabb et al., 2002; Magnusson et al., 2005; Wang et al., 2010). Several clinical trials have tried using anti‐inflammatory agents to target the complement system and systemic inflammation, but these had limited success (Ambati, Atkinson & Gelfand, 2013).…”

Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study

“…Some studies have included groups of individuals with conditions labelled as early AMD 23,24 or low-risk AMD, 12 whereas others investigated in more detail how genetic variants relate to specific morphologic features of early AMD. 12,[24][25][26][27][28][29] These studies reported that the allelic risk variants of the CFH gene were more frequent among early AMD cases compared with controls but that the risk was much stronger among patients with more advanced disease. 12,[24][25][26]29 Similarly, Rivera et al 12 showed for the ARMS2-rs10490924 variant, a slightly higher frequency in patients with early AMD, whereas substantially increased frequencies were observed in patients with late AMD.…”

“…12,[24][25][26][27][28][29] These studies reported that the allelic risk variants of the CFH gene were more frequent among early AMD cases compared with controls but that the risk was much stronger among patients with more advanced disease. 12,[24][25][26]29 Similarly, Rivera et al 12 showed for the ARMS2-rs10490924 variant, a slightly higher frequency in patients with early AMD, whereas substantially increased frequencies were observed in patients with late AMD. Recently, it was hypothesised that genetic variations in the CFH locus contributed to global and diffuse retinal disease, including early maculopathy and extramacular parts of the retina, while the ARMS2 variant and HtrA1-rs11200638 appeared mainly related to the angiogenic pathway and specifically to neovascularisation.…”

The LOC387715 Polymorphism, Inflammatory Markers, Smoking, and Age-Related Macular Degeneration

“…20,22,23 Combined genetic and environmental effects, gene-environment interactions, or both are key findings in understanding the mechanisms of this disease. 24,25 Recently, many studies using clinical cases and control samples have identified different AMDrelated gene variants, including a complement factor H (CFH) polymorphism at chromosome 1q31 [26][27][28][29][30][31][32]33,34 and HTRA1 35,36 at chromosome 10q26. The effects of interactions between CFH gene variants and some systemic and environmental factors on the risk of AMD were recently investigated in a clinic-based sample, the Age-Related Eye Disease Study, 25,37 and a population-based sample in Netherlands.…”