Toll-like receptor polymorphisms and age-related macular degeneration
Toll-like receptor polymorphisms and age-related macular degeneration
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DOI：
10.1167/iovs.07-1378
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发表时间：
2008-04-01
影响因子：
4.4
通讯作者：
Tosakulwong, Nirubol
中科院分区：
文献类型：
--
作者：
Edwards, Albert O.;Chen, Dequan;Tosakulwong, Nirubol
目的.来自遗传相关性研究的证据以及视网膜和脉络膜中补体沉积的证据表明，先天免疫的非细胞途径在年龄相关性黄斑变性（AMD）的发病机制中起作用。本研究的目的是确定10种人类Toll样受体（TLR）的常见变异是否会改变AMD的风险。在577名受试者（有或没有AMD）的队列中，对TLR基因中的68个SNP进行迭代基因分型。另外两个队列用于复制研究。标准的遗传关联方法被用来分析与疾病的关联和与其他位点的相互作用的结果。TLR3（rs3775291）和TLR7（rs179008）中的编码SNP在多重检验校正前显示与一组中的AMD相关（分别为P = 0.01和P = 0.02）。对于这两个SNP，与AMD的关联是由于与主要等位基因的纯合子相比，杂合子过多。在另一个病例对照队列或大家族队列中，这两个编码SNP与AMD无关。尽管TLR4基因内含子SNP与AMD的发生有一定的相关性（P = 0.03），但不可能复制以前与该基因中罕见的编码SNP D299G的相关性（P = 0.6）。尽管在某些队列中报告了TLR基因多态性与AMD之间关联的临界支持，但未重复这些在TLR3、TLR4和TLR7中编码SNP的初始观察结果。TLR变异不太可能对总体AMD风险产生重大影响，研究的常见变异与AMD无关。
PURPOSE. Evidence from genetic-association studies in conjunction with the demonstration of complement deposition in the retina and choroid implicates noncellular pathways of innate immunity in the pathogenesis of age-related macular degeneration (AMD). The purpose of this study was to determine whether common variation in the 10 human toll-like receptors (TLRs) alters the risk of AMD.METHODS. Sixty-eight SNPs were iteratively genotyped across the TLR genes in a cohort of 577 subjects, with and without AMD. Two additional cohorts were used for replication studies. Standard genetic-association methods were used to analyze the results for association with disease and interaction with other loci.RESULTS. Coding SNPs in TLR3 (rs3775291) and TLR7 (rs179008) showed association with AMD in one group ( P = 0.01 and P = 0.02, respectively) before correction for multiple testing. For both SNPs, the association with AMD arose due to an excess of heterozygotes compared with homozygotes for the major allele. The two coding SNPs were not associated with AMD in another case - control cohort or an extended-family cohort. Although an intronic SNP in TLR4 was associated marginally with AMD ( P = 0.03), it was not possible to replicate a previous association with the rare coding SNP D299G in this gene ( P = 0.6).CONCLUSIONS. Although borderline support for association between polymorphisms in TLR genes and AMD was reported for some cohorts, these initial observations of coding SNPs in TLR3, TLR4, and TLR7 were not replicated. TLR variants are unlikely to have a major impact on overall AMD risk, and the common variants studied were not associated with AMD.