拷贝数多态性与年龄相关性黄斑变性风险的关联性评估。
Association assessment of copy number polymorphism and risk of age-related macular degeneration.
机构信息
SAIC-Frederick, Inc, Frederick, Maryland, USA.
出版信息
Ophthalmology. 2011 Dec;118(12):2442-6. doi: 10.1016/j.ophtha.2011.05.027.
PURPOSE
We previously identified a genetic copy number polymorphism (CNP147) that was statistically associated with age-related macular degeneration (AMD) and that resides downstream of the complement factor H (CFH) gene. Factor H protein is polymorphic at amino acid 402, in which the resulting histidine containing moiety has been established to impart significant risk of AMD. We present a method to precisely determine the exact copy number of CNP147 and examine in more detail the association with AMD.
DESIGN
Case-control study.
PARTICIPANTS
A total of 421 Age-Related Eye Disease Study (AREDS) subjects, of whom approximately 35% were diagnosed with neovascular disease, 19% were diagnosed with geographic atrophy, 16% were diagnosed with both, 30% were diagnosed with large drusen, and 215 were controls.
METHODS
By using copy number assays available from Applied Biosystems Inc. (Carlsbad, CA), we examined 4 loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. We analyzed these data by copy number while controlling for 2 high-risk CFH variants, rs1061170 (Y402H) and rs1410996. We phased the high-risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To further validate copy numbers, 6 Utah Centre D'etude du Polymorphism Humaine (CEPH) families were typed for CNP147, and the segregation was assessed.
MAIN OUTCOME MEASURES
Increased or decreased risk of AMD from genetic loci.
RESULTS
Having fewer than 2 copies of CNP147 was associated with an estimated 43% reduction in odds of having AMD in this sample set (adjusted odds ratio [OR] = 0.57, P=0.006). CNP148 variation is rare in Caucasians and was not statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate with higher copy numbers for CNP147, but not exclusively, and that 1 haplotype that carried a deletion of CNP147 was highly protective (OR = 0.25 P=1.3×10(-13)) when compared with the reference.
CONCLUSIONS
In this matched subset of AREDS subjects, after adjusting for 2 known risk variants in CFH, CNP147 deletion statistically associates with diminished risk for AMD.
FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
目的
我们先前确定了一个与年龄相关性黄斑变性（AMD）相关的遗传拷贝数多态性（CNP147），它位于补体因子 H（CFH）基因下游。因子 H 蛋白在氨基酸 402 处存在多态性，其中含组氨酸的部分已被确定赋予 AMD 的显著风险。我们提出了一种精确确定 CNP147 的确切拷贝数的方法，并更详细地研究了其与 AMD 的关联。
设计
病例对照研究。
参与者
总共 421 名年龄相关性眼病研究（AREDS）受试者，其中约 35%被诊断为新生血管性疾病，19%被诊断为地理萎缩，16%同时被诊断为两者，30%被诊断为大 drusen，215 名为对照。
方法
通过使用来自 Applied Biosystems Inc.（加利福尼亚州卡尔斯巴德）的拷贝数检测，我们在一个 AREDS 匹配的病例对照样本集中检查了跨越 CNP147 和相邻 CNP148 的 4 个基因座。我们在控制 2 个高风险 CFH 变异体 rs1061170（Y402H）和 rs1410996 的情况下，通过拷贝数分析这些数据。我们对高风险 CFH 变异体与 CNP147 进行了相位分析，并分析了病例和对照组中的单倍型频率。为了进一步验证拷贝数，对 6 个犹他州人类多态性研究中心（CEPH）家族进行了 CNP147 分型，并评估了其分离情况。
主要观察指标
来自遗传基因座的 AMD 风险增加或降低。
结果
在该样本集中，CNP147 拷贝数少于 2 个与 AMD 发生的几率估计降低 43%相关（调整后的优势比[OR] = 0.57，P = 0.006）。CNP148 变异在白种人中很少见，且无统计学意义。常见单倍型表明，rs1061170 和 rs1410996 的风险等位基因最常与 CNP147 的高拷贝数相关，但并非排他性的，并且携带 CNP147 缺失的 1 个单倍型与参考相比具有高度保护作用（OR = 0.25，P = 1.3×10（-13））。
结论
在 AREDS 受试者的这个匹配子集中，在调整了 CFH 中的 2 个已知风险变异体后，CNP147 缺失与 AMD 风险降低呈统计学关联。
金融披露
作者没有与本文讨论的任何材料有关的专有或商业利益。
Zotero 插件