Pathway analysis of single-nucleotide polymorphisms potentially associated with glioblastoma multiforme susceptibility using random forests
Pathway analysis of single-nucleotide polymorphisms potentially associated with glioblastoma multiforme susceptibility using random forests
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DOI：
10.1158/1055-9965.epi-07-2830
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发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Wrensch, Margaret R.
中科院分区：
文献类型：
--
作者：
Chang, Jeffrey S.;Yeh, Ru-Fang;Wrensch, Margaret R.
神经胶质瘤是一种复杂的疾病，不太可能由单个基因的作用引起。涉及多个基因的通路水平的遗传分析可能比一次分析一个基因更有可能捕获基因-疾病关联。目前的初步研究包括112名患有多形性胶质母细胞瘤的高加索人和112名高加索健康对照，其频率与年龄和性别相匹配。受试者使用市售的（ParAllele/Affyssin）检测组进行基因分型，该检测组包含10，177个非同义编码单核苷酸多态性（SNP），涵盖构建该检测组时已知的基因组。对于该分析，我们选择了10个可能参与胶质瘤发生的通路，这些通路在面板上具有SNP。我们对每个通路组内的SNP进行随机森林（RF）分析和逻辑回归，以评估RF预测误差优于机会且排列P < 0.10的一个通路中基因之间的相互作用。只有DNA修复途径有一个更好的机会分类的病例对照状态的预测误差为45.5%和P = 0.09。DNA修复途径的三个SNP（EXO 1的rs 1047840、EME 1的rs 12450550和BRCA 1的rs799917）被鉴定为有希望的进一步复制的候选者。此外，EXO 1的rs 1047840与BRCA 1的rs799917或rs 1799966之间观察到统计学显著的相互作用（P < 0.05）。尽管与胶质瘤相关的基因和SNP不完全包含，并且样本量小，RF分析确定了一个重要的生物学途径和几个可能与胶质母细胞瘤发展相关的SNP。
Glioma is a complex disease that is unlikely to result from the effect of a single gene. Genetic analysis at the pathway level involving multiple genes may be more likely to capture gene-disease associations than analyzing genes one at a time. The current pilot study included 112 Caucasians with glioblastoma multiforme and 112 Caucasian healthy controls frequency matched to cases by age and gender. Subjects were genotyped using a commercially available (ParAllele/Affymetrix) assay panel of 10,177 nonsynonymous coding single-nucleotide polymorphisms (SNP) spanning the genome known at the time the panel was constructed. For this analysis, we selected 10 pathways potentially involved in gliomagenesis that had SNPs represented on the panel. We performed random forests (RF) analyses of SNPs within each pathway group and logistic regression to assess interaction among genes in the one pathway for which the RF prediction error was better than chance and the permutation P < 0.10. Only the DNA repair pathway had a better than chance classification of case-control status with a prediction error of 45.5% and P = 0.09. Three SNPs (rs1047840 of EXO1, rs12450550 of EME1, and rs799917 of BRCA1) of the DNA repair pathway were identified as promising candidates for further replication. In addition, statistically significant interactions (P < 0.05) between rs1047840 of EXO1 and rs799917 or rs1799966 of BRCA1 were observed. Despite less than complete inclusion of genes and SNPs relevant to glioma and a small sample size, RF analysis identified one important biological pathway and several SNPs potentially associated with the development of glioblastoma.