Abstract
Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass index (BMI), and potential associations of C-reactive protein, factor H related-2 (FHR-2) and collectin-11 with AMD. In addition, we confirmed previously described associations and identified new associations of AMD variants with complement levels. New associations include increased C4 levels for rs181705462 at the C2/CFB locus, decreased vitronectin (VTN) levels for rs11080055 at the TMEM97/VTN locus and decreased factor I levels for rs10033900 at the CFI locus. Finally, we detected significant associations between AMD-associated metabolites and complement proteins in plasma. The most significant complement-metabolite associations included increased high density lipoprotein (HDL) subparticle levels with decreased C3, factor H (FH) and VTN levels. The results of our study indicate that demographic factors, genetic variants and circulating metabolites are associated with complement protein components. We suggest that these factors should be considered to design personalized treatment approaches and to increase the success of clinical trials targeting the complement system.
Highlights
Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world
Using a multiplex selected reaction monitoring (SRM) liquid chromatography–mass spectrometry (MS) assay [34], levels of 64 peptides from 32 proteins of the complement system were measured in 476 plasma samples
In this study we performed a comprehensive analysis of 32 complement proteins in plasma samples of AMD patients using mass spectrometry-based semi-quantitative multiplex profiling [34]
Summary
Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The drusen expand and coalesce, leading to two types of advanced stages. Geographic atrophy (GA) is defined by atrophy of photoreceptors, RPE and choriocapillaris in the macula, leading to progressive and irreversible loss of central vision. Neovascular AMD (nAMD) is characterized by the abnormal ingrowth of new blood vessels from the choriocapillaris into the sub-RPE or subretinal space. These aberrant vessels are fragile and tend to leak fluid and blood, causing rapid and severe vision loss. Neovascularization in nAMD can effectively be treated with intravitreal injections of anti-vascular endothelial growth factor (VEGF), but no approved treatment is currently available to prevent degeneration in GA
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