Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration
Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration
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DOI：
10.1086/503822
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发表时间：
2006-05-01
影响因子：
9.8
通讯作者：
Pericak-Vance, MA
中科院分区：
文献类型：
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作者：
Schmidt, S;Hauser, MA;Pericak-Vance, MA
我们使用迭代关联作图来确定染色体10 q26上年龄相关性黄斑变性（AMD）的易感基因，该基因是这种疾病最一致的关联区域之一。我们采用连锁分析方法，其次是家庭为基础的和病例对照关联分析，使用两个独立的数据集。为了从统计学上确定最可能的AMD易感等位基因，我们使用了基因型-IBD共享测试（GIST）和条件单倍型分析。为了纳入两个最重要的已知AMD风险因素-吸烟和补体因子H基因（CFH）的Y 402 H变体-我们使用逻辑回归模型来测试病例对照数据集中的基因-基因和基因-环境相互作用，并使用有序子集分析来解释基于家族的数据集中的遗传连锁异质性。我们的研究结果强烈暗示编码变化（Ala 69 Ser）在LOC 387715基因作为第二个主要的AMD易感等位基因，证实了早期的建议。该变体对AMD的作用在统计学上独立于CFH，并且与Y 402 H的作用具有相似的量级。总体效应主要由吸烟者中的强关联驱动，因为我们观察到LOC 387715变体与吸烟史之间存在统计学相互作用的显著证据。这种基因-环境相互作用得到了统计学独立的基于家系和病例对照分析方法的支持。我们估计CFH、LOC 387715和吸烟共同解释了61%的AMD人群归因风险（PAR）。调整后的PAR百分比估计值为吸烟20%，LOC 387715 36%，CFH 43%。我们首次证明，遗传易感性与可改变的生活方式因素（如吸烟）相结合，比单独的任何一个因素都能显著提高AMD的风险。
We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analysis. To incorporate the two most important known AMD risk factors-smoking and the Y402H variant of the complement factor H gene (CFH) - we used logistic regression modeling to test for gene-gene and gene-environment interactions in the case-control data set and used the ordered-subset analysis to account for genetic linkage heterogeneity in the family-based data set. Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major identified AMD-susceptibility allele, confirming earlier suggestions. This variant's effect on AMD is statistically independent of CFH and is of similar magnitude to the effect of Y402H. The overall effect is driven primarily by a strong association in smokers, since we observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction is supported by statistically independent family-based and case-control analysis methods. We estimate that CFH, LOC387715, and cigarette smoking together explain 61% of the population-attributable risk (PAR) of AMD. The adjusted PAR percentage estimates are 20% for smoking, 36% for LOC387715, and 43% for CFH. We demonstrate, for the first time, that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.