Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).
Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).
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DOI：
10.1186/s12974-016-0548-0
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发表时间：
2016-04-18
影响因子：
9.3
通讯作者：
Baird PN
中科院分区：
文献类型：
--
作者：
Grassmann F;Cantsilieris S;Schulz-Kuhnt AS;White SJ;Richardson AJ;Hewitt AW;Vote BJ;Schmied D;Guymer RH;Weber BH;Baird PN
视网膜相关性黄斑变性（AMD）是西方社会视力丧失的主要原因，具有很强的遗传成分。候选基因研究以及全基因组关联研究强烈暗示补体基因的遗传变异与疾病风险有关。到目前为止，还没有报道AMD与补体成分4（C4）的相关性，这可能是由于6号染色体上C4基因座的复杂性。我们使用多重连接依赖性探针扩增（MLPA），以确定C4基因的拷贝数，以及两个相关的亚型，C4 A和C4 B，并评估其与AMD使用逻辑回归模型。在这里，我们报告的2645个人（1536先证者和1109未受影响的控制），在三个不同的中心，多等位基因拷贝数变异（CNV）在C4位点的分析。我们发现C4 A拷贝数增加的相关性具有很强的统计学意义（OR 0.81（0.73; 0.89）;P = 4.4 × 10−5），其中78岁以上的个体（OR 0.67（0.55; 0.81））和女性（OR 0.77（0.68; 0.87））的影响最为明显。此外，这种关联不依赖于附近CFB/C2基因座中已知的AMD相关风险变异，特别是在女性和78岁以上的个体中。我们的数据强化了补体失调在AMD病因学中起关键作用的概念，这是早期干预策略和未来治疗的重要发现。此外，我们首次提供了多等位基因CNV与AMD病理学相关的证据。本文的在线版本（doi：10.1186/s12974-016-0548-0）包含补充材料，可供授权用户使用。
Age-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6. We used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of the C4 gene as well as of both relevant isoforms, C4A and C4B, and assessed their association with AMD using logistic regression models. Here, we report on the analysis of 2645 individuals (1536 probands and 1109 unaffected controls), across three different centers, for multiallelic copy number variation (CNV) at the C4 locus. We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10−5), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)). Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years. Our data strengthen the notion that complement dysregulation plays a crucial role in AMD etiology, an important finding for early intervention strategies and future therapeutics. In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology. The online version of this article (doi:10.1186/s12974-016-0548-0) contains supplementary material, which is available to authorized users.