Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Ophthalmology. 2018 Jul;125(7):1064-1074. doi: 10.1016/j.ophtha.2017.12.023. Epub 2018 Feb 2.
To identify genetic variants associated with complement activation, which may help to select age-related macular degeneration (AMD) patients for complement-inhibiting therapies.
Genome-wide association study (GWAS) followed by replication and meta-analysis.
AMD patients and controls (n = 2245).
A GWAS on serum C3d-to-C3 ratio was performed in 1548 AMD patients and controls. For replication and meta-analysis, 697 additional individuals were genotyped. A model for complement activation including genetic and non-genetic factors was built, and the variance explained was estimated. Haplotype analysis was performed for 8 SNPs across the CFH/CFHR locus. Association with AMD was performed for the variants and haplotypes found to influence complement activation.
Normalized C3d/C3 ratio as a measure of systemic complement activation.
Complement activation was associated independently with rs3753396 located in CFH (P = 1.09 × 10; P = 3.66 × 10; β = 0.141; standard error [SE] = 0.015) and rs6685931 located in CFHR4 (P = 8.18 × 10; P = 6.32 × 10; β = 0.054; SE = 0.010). A model including age, AMD disease status, body mass index, triglycerides, rs3753396, rs6685931, and previously identified SNPs explained 18.7% of the variability in complement activation. Haplotype analysis revealed 3 haplotypes (H1-2 and H6 containing rs6685931 and H3 containing rs3753396) associated with complement activation. Haplotypes H3 and H6 conferred stronger effects on complement activation compared with the single variants (P = 2.53 × 10; β = 0.183; SE = 0.024; and P = 4.28 × 10; β = 0.144; SE = 0.041; respectively). Association analyses with AMD revealed that SNP rs6685931 and haplotype H1-2 containing rs6685931 were associated with a risk for AMD development, whereas SNP rs3753396 and haplotypes H3 and H6 were not.
The SNP rs3753396 in CFH and SNP rs6685931 in CFHR4 are associated with systemic complement activation levels. The SNP rs6685931 in CFHR4 and its linked haplotype H1-2 also conferred a risk for AMD development, and therefore could be used to identify AMD patients who would benefit most from complement-inhibiting therapies.
确定与补体激活相关的遗传变异，这可能有助于选择年龄相关性黄斑变性（AMD）患者进行补体抑制治疗。
全基因组关联研究（GWAS），随后进行复制和荟萃分析。
AMD 患者和对照（n=2245）。
对 1548 名 AMD 患者和对照的血清 C3d-to-C3 比值进行了 GWAS。为了复制和荟萃分析，对另外 697 个人进行了基因分型。建立了一个包括遗传和非遗传因素的补体激活模型，并估计了方差解释。对 CFH/CFHR 基因座的 8 个 SNP 进行了单倍型分析。对影响补体激活的变体和单倍型进行了与 AMD 的关联分析。
作为系统补体激活衡量标准的正常化 C3d/C3 比值。
补体激活与位于 CFH 的 rs3753396（P=1.09×10；P=3.66×10；β=0.141；标准误差 [SE] =0.015）和位于 CFHR4 的 rs6685931（P=8.18×10；P=6.32×10；β=0.054；SE=0.010）独立相关。一个包括年龄、AMD 疾病状态、体重指数、甘油三酯、rs3753396、rs6685931 和先前确定的 SNPs 的模型解释了补体激活变异的 18.7%。单倍型分析显示 3 个单倍型（包含 rs6685931 的 H1-2 和 H6 以及包含 rs3753396 的 H3）与补体激活相关。与单个变体相比，单倍型 H3 和 H6 对补体激活的影响更强（P=2.53×10；β=0.183；SE=0.024；P=4.28×10；β=0.144；SE=0.041）。与 AMD 的关联分析显示，SNP rs6685931 和包含 rs6685931 的单倍型 H1-2 与 AMD 发病风险相关，而 SNP rs3753396 和单倍型 H3 和 H6 则不相关。
CFH 中的 SNP rs3753396 和 CFHR4 中的 SNP rs6685931 与系统性补体激活水平相关。CFHR4 中的 SNP rs6685931 及其相关的单倍型 H1-2 也与 AMD 的发病风险相关，因此可用于识别最受益于补体抑制治疗的 AMD 患者。
