Ristau Tina, Paun Constantin, Ersoy Lebriz, Hahn Moritz, Lechanteur Yara, Hoyng Carel, de Jong Eiko K, Daha Mohamed R, Kirchhof Bernd, den Hollander Anneke I, Fauser Sascha
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
PLoS One. 2014 Mar 27;9(3):e93459. doi: 10.1371/journal.pone.0093459. eCollection 2014.
Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56 × 10(-7)), AMD phenotype (p = 1.15 × 10(-11)) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87 × 10(-6)), higher body mass index (p = 1.00 × 10(-13)), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60 × 10(-6)) in CFH, rs4151667 (p = 1.01 × 10(-5)) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation.
年龄相关性黄斑变性（AMD）是一种常见疾病，可导致严重视力丧失，补体系统失调被认为与该疾病有关。为了研究AMD易感基因中的多态性与全身补体激活之间的关联，对23个AMD相关风险基因内部或附近的32个单核苷酸多态性（SNP）对2655名个体进行了基因分型。在血清中测量了补体成分3（C3）及其分解代谢片段C3d，并使用多模态成像进行了AMD分期。计算了C3d/C3比值，并分析了其与环境因素、SNP以及补体因子H（CFH）基因和补体因子B（CFB）基因的各种单倍型之间的关联。建立线性模型以测量基因变异对C3d/C3比值的影响。研究队列包括1387例AMD患者和1268名对照。发现当前吸烟者（p = 0.002）、较高年龄（p = 1.56×10⁻⁷）、AMD表型（p = 1.15×10⁻¹¹）以及C3基因中的两个SNP rs6795735（p = 0.04）和rs2230199（p = 0.04）的C3d/C3比值较高。发现糖尿病（p = 2.87×10⁻⁶）、较高体重指数（p = 1.00×10⁻¹³）、CFH中的SNP rs1410996（p = 0.0001）、rs800292（p = 0.003）、rs12144939（p = 4.60×10⁻⁶）、CFB中的rs4151667（p = 1.01×10⁻⁵）以及CFH和CFB中的个体单倍型的C3d/C3比值较低。线性模型显示校正决定系数R²为0.063，包括年龄、吸烟状况、性别和基因多态性，解释了C3d/C3比值的6.3%。加入AMD状态后，校正决定系数R²为0.067。总之，除了C3基因中的两个SNP外，所评估的基因多态性均未显示与全身补体激活增加有关。AMD的主要遗传和非遗传因素与全身补体激活无关。
