Triebwasser Michael P, Roberson Elisha D O, Yu Yi, Schramm Elizabeth C, Wagner Erin K, Raychaudhuri Soumya, Seddon Johanna M, Atkinson John P
Washington University School of Medicine Department of Internal Medicine, Division of Rheumatology, St. Louis, Missouri, United States.
Washington University School of Medicine Department of Internal Medicine, Division of Rheumatology, St. Louis, Missouri, United States 2Washington University School of Medicine, Department of Genetics, St. Louis, Missouri, United States.
Invest Ophthalmol Vis Sci. 2015 Oct;56(11):6873-8. doi: 10.1167/iovs.15-17432.
Age-related macular degeneration (AMD) has a substantial genetic risk component, as evidenced by the risk from common genetic variants uncovered in the first genome-wide association studies. More recently, it has become apparent that rare genetic variants also play an independent role in AMD risk. We sought to determine if rare variants in complement factor H (CFH) played a role in AMD risk.
We had previously collected DNA from a large population of patients with advanced age-related macular degeneration (A-AMD) and controls for targeted deep sequencing of candidate AMD risk genes. In this analysis, we tested for an increased burden of rare variants in CFH in 1665 cases and 752 controls from this cohort.
We identified 65 missense, nonsense, or splice-site mutations with a minor allele frequency ≤ 1%. Rare variants with minor allele frequency ≤ 1% (odds ratio [OR] = 1.5, P = 4.4 × 10⁻²), 0.5% (OR = 1.6, P = 2.6 × 10⁻²), and all singletons (OR = 2.3, P = 3.3 × 10⁻²) were enriched in A-AMD cases. Moreover, we observed loss-of-function rare variants (nonsense, splice-site, and loss of a conserved cysteine) in 10 cases and serum levels of FH were decreased in all 5 with an available sample (haploinsufficiency). Further, rare variants in the major functional domains of CFH were increased in cases (OR = 3.2; P = 1.4 × 10⁻³) and the magnitude of the effect correlated with the disruptive nature of the variant, location in an active site, and inversely with minor allele frequency.
In this large A-AMD cohort, rare variants in the CFH gene were enriched and tended to be located in functional sites or led to low serum levels. These data, combined with those indicating a similar, but even more striking, increase in rare variants found in CFI, strongly implicate complement activation in A-AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway.
年龄相关性黄斑变性（AMD）具有显著的遗传风险成分，这在首批全基因组关联研究中发现的常见遗传变异所带来的风险中得到了证实。最近，很明显罕见遗传变异在AMD风险中也发挥着独立作用。我们试图确定补体因子H（CFH）中的罕见变异是否在AMD风险中起作用。
我们之前从大量晚期年龄相关性黄斑变性（A-AMD）患者和对照人群中收集了DNA，用于对候选AMD风险基因进行靶向深度测序。在该分析中，我们检测了来自该队列的1665例患者和752例对照中CFH罕见变异的负担是否增加。
我们鉴定出65个错义、无义或剪接位点突变，其次要等位基因频率≤1%。次要等位基因频率≤1%（优势比[OR]=1.5，P=4.4×10⁻²）、0.5%（OR=1.6，P=2.6×10⁻²）的罕见变异以及所有单倍型（OR=2.3，P=3.3×10⁻²）在A-AMD病例中富集。此外，我们在10例患者中观察到功能丧失的罕见变异（无义、剪接位点和保守半胱氨酸的缺失），并且在所有5例有可用样本的患者中（单倍剂量不足）血清FH水平降低。此外，CFH主要功能域中的罕见变异在病例中增加（OR=3.2；P=1.4×10⁻³），并且效应的大小与变异的破坏性性质、在活性位点的位置相关，与次要等位基因频率呈负相关。
在这个大型A-AMD队列中，CFH基因中的罕见变异富集，并且倾向于位于功能位点或导致血清水平降低。这些数据，与那些表明在CFI中发现的罕见变异有类似但更显著增加的数据相结合，强烈提示补体激活在A-AMD发病机制中起作用，因为CFH和CFI相互作用以抑制替代途径。
