Yamada Yoshiji, Sakuma Jun, Takeuchi Ichiro, Yasukochi Yoshiki, Kato Kimihiko, Oguri Mitsutoshi, Fujimaki Tetsuo, Horibe Hideki, Muramatsu Masaaki, Sawabe Motoji, Fujiwara Yoshinori, Taniguchi Yu, Obuchi Shuichi, Kawai Hisashi, Shinkai Shoji, Mori Seijiro, Arai Tomio, Tanaka Masashi
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.
CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
Int J Mol Med. 2017 May;39(5):1091-1100. doi: 10.3892/ijmm.2017.2927. Epub 2017 Mar 21.
We performed an exome-wide association study (EWAS) to identify genetic variants - in particular, low‑frequency or rare variants with a moderate to large effect size - that confer susceptibility to aortic aneurysm with 8,782 Japanese subjects (456 patients with aortic aneurysm, 8,326 control individuals) and with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The correlation of allele frequencies for 41,432 single nucleotide polymorphisms (SNPs) that passed quality control to aortic aneurysm was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21x10-6 was considered statistically significant. The EWAS revealed 59 SNPs that were significantly associated with aortic aneurysm. None of these SNPs was significantly (P<2.12x10-4) associated with aortic aneurysm by multivariable logistic regression analysis with adjustment for age, gender and hypertension, although 8 SNPs were related (P<0.05) to this condition. Examination of the correlation of these latter 8 SNPs to true or dissecting aortic aneurysm separately showed that rs1465567 [T/C (W229R)] of the EGF-like, fibronectin type III, and laminin G domains gene (EGFLAM) (dominant model; P=0.0014; odds ratio, 1.63) was significantly (P<0.0016) associated with true aortic aneurysm. We next performed EWASs for true or dissecting aortic aneurysm separately and found that 45 and 19 SNPs were significantly associated with these conditions, respectively. Multivariable logistic regression analysis with adjustment for covariates revealed that rs113710653 [C/T (E231K)] of the spermatogenesis- and centriole associated 1-like gene (SPATC1L) (dominant model; P=0.0002; odds ratio, 5.32) and rs143881017 [C/T (R140H)] of the ribonuclease A family member 13 gene (RNASE13) (dominant model; P=0.0006; odds ratio, 5.77) were significantly (P<2.78x10-4 or P<6.58x10-4, respectively) associated with true or dissecting aortic aneurysm, respectively. EGFLAM and SPATC1L may thus be susceptibility loci for true aortic aneurysm and RNASE13 may be such a locus for dissecting aneurysm in Japanese individuals.
我们开展了一项全外显子组关联研究（EWAS），以识别基因变异——尤其是具有中度至较大效应大小的低频或罕见变异——这些变异会使日本的8782名受试者（456例主动脉瘤患者和8326名对照个体）易患主动脉瘤，研究使用了Illumina HumanExome-12 DNA分析芯片或Infinium Exome-24芯片阵列。通过Fisher精确检验，检查了41432个通过质量控制的单核苷酸多态性（SNP）的等位基因频率与主动脉瘤的相关性。基于Bonferroni校正，P值<1.21×10⁻⁶被认为具有统计学意义。该全外显子组关联研究揭示了59个与主动脉瘤显著相关的SNP。在对年龄、性别和高血压进行校正的多变量逻辑回归分析中，这些SNP均与主动脉瘤无显著相关性（P<2.12×10⁻⁴），尽管有8个SNP与此病症相关（P<0.05）。对这后8个SNP与真性或夹层主动脉瘤的相关性分别进行检查，结果显示，表皮生长因子样、纤连蛋白III型和层粘连蛋白G结构域基因（EGFLAM）的rs1465567 [T/C (W229R)]（显性模型；P = 0.0014；优势比，1.63）与真性主动脉瘤显著相关（P<0.0016）。接下来，我们分别对真性或夹层主动脉瘤进行了全外显子组关联研究，发现分别有45个和19个SNP与这些病症显著相关。对协变量进行校正的多变量逻辑回归分析显示，精子发生和中心粒相关1样基因（SPATC1L）的rs113710653 [C/T (E231K)]（显性模型；P = 0.0002；优势比，5.32）和核糖核酸酶A家族成员13基因（RNASE13）的rs143881017 [C/T (R140H)]（显性模型；P = 0.0006；优势比，5.77）分别与真性或夹层主动脉瘤显著相关（分别为P<2.78×10⁻⁴或P<6.58×10⁻⁴）。因此，EGFLAM和SPATC1L可能是日本人真性主动脉瘤的易感基因座，而RNASE13可能是夹层主动脉瘤的此类基因座。
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