Center for Human Genetics, School of Medicine, Duke University Medical Center, Box 3382, Durham, NC, 27710, USA,
Hum Genet. 2013 Dec;132(12):1371-82. doi: 10.1007/s00439-013-1339-7. Epub 2013 Aug 2.
We performed a gene-smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene-smoking interaction at P < 0.05 using association in the presence of linkage--ordered subset analysis, a method that uses permutations of the data to empirically estimate the strength of the association signal. Seven of the 16 SNPs were in the Rho-GTPase pathway indicating a 1.87-fold enrichment for this pathway. A meta-analysis of gene-smoking interactions in three independent studies revealed that rs9289231 in KALRN had a Fisher's combined P value of 0.0017 for the interaction with smoking. In a gene-based meta-analysis KALRN had a P value of 0.026. Finally, a pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.
我们使用早发性冠状动脉疾病队列（GENECARD）的家族进行了基因-吸烟相互作用分析。这项分析的重点是验证和扩展先前研究的结果，这些研究表明染色体 3 上的单核苷酸多态性（SNP）与吸烟介导的冠状动脉疾病有关。我们分析了染色体 3 上的 430 个 SNP，并使用连锁有序子集分析（一种使用数据置换来经验估计关联信号强度的方法）在存在连锁的情况下对关联进行分析，确定了 16 个在 P < 0.05 时表现出基因-吸烟相互作用的 SNP。这 16 个 SNP 中有 7 个位于 Rho-GTPase 途径中，表明该途径的富集倍数为 1.87 倍。对三项独立研究中的基因-吸烟相互作用进行的荟萃分析表明，KALRN 中的 rs9289231 与吸烟的相互作用的 Fisher 综合 P 值为 0.0017。在基于基因的荟萃分析中，KALRN 的 P 值为 0.026。最后，使用 WebGestalt 对关联结果进行基于途径的分析揭示了几个富集途径，包括京都基因和基因组百科全书定义的肌动蛋白细胞骨架途径的调节。
