Dungan Jennifer R, Qin Xue, Hurdle Melissa, Haynes Carol S, Hauser Elizabeth R, Kraus William E
Division of Healthcare in Adult Populations, School of Nursing, Duke University, Durham, NC, United States.
School of Medicine, Duke Molecular Physiology Institute, Duke University, Durham, NC, United States.
Front Genet. 2021 Jun 1;12:661497. doi: 10.3389/fgene.2021.661497. eCollection 2021.
Coronary artery disease (CAD) is an age-associated condition that greatly increases the risk of mortality. The purpose of this study was to identify gene variants associated with all-cause mortality among individuals with clinically phenotyped CAD using a genome-wide screening approach.
We performed discovery ( = 1,099), replication ( = 404), and meta-analyses ( = 1,503) for association of genomic variants with survival outcome using secondary data from White participants with CAD from two GWAS sub-studies of the Duke Catheterization Genetics Biorepository. We modeled time from catheterization to death or last follow-up (median 7.1 years, max 12 years) using Cox multivariable regression analysis. Target statistical screening thresholds were × 10 for the discovery phase and Bonferroni-calculated -values for the replication ( < 5.3 × 10) and meta-analysis ( < 1.6 × 10) phases. Genome-wide analysis of 785,945 autosomal SNPs revealed two SNPs (rs13007553 and rs587936) that had the same direction of effect across all three phases of the analysis, with suggestive -value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, , which resides between and , conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17-1.86, = 1.07 × 10 (discovery), = 0.03 (replication), = 9.53 × 10 (meta-analysis)]. is involved in neuronal differentiation. is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to was associated with increased survival time [HR , 95% CI -0.83, = 4.79 × 10 (discovery), = 0.02 (replication), = 2.25 × 10 (meta-analysis)]. is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. has multiple lines of evidence for protection against atherosclerosis.
Replicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci (rs13007553) and biologically relevant candidate (rs587936). These candidates did not overlap with validated longevity candidate genes. Future research could further define the role of common variants in survival outcomes for people with CAD and, ultimately, improve longitudinal outcomes for these patients.
冠状动脉疾病（CAD）是一种与年龄相关的疾病，会大幅增加死亡风险。本研究的目的是使用全基因组筛查方法，在具有临床表型的CAD个体中识别与全因死亡率相关的基因变异。
我们利用来自杜克导管插入遗传学生物样本库两项GWAS子研究的白人CAD参与者的二级数据，对基因组变异与生存结果的关联进行了发现性研究（n = 1099）、重复性研究（n = 404）和荟萃分析（n = 1503）。我们使用Cox多变量回归分析对从导管插入到死亡或最后一次随访的时间（中位数7.1年，最长12年）进行建模。发现阶段的目标统计筛查阈值为p×10，重复性研究（p < 5.3×10）和荟萃分析（p < 1.6×10）阶段为Bonferroni计算的p值。对785,945个常染色体单核苷酸多态性（SNP）进行全基因组分析，发现两个SNP（rs13007553和rs587936）在分析的所有三个阶段都具有相同的效应方向，在发现性研究和重复性研究中具有提示性p值关联，在调整临床协变量的模型中具有显著的荟萃分析关联。rs13007553 SNP变异体，位于……和……之间，即使在控制临床协变量后，也会增加全因死亡率风险[风险比（HR）1.47，95%置信区间（CI）1.17 - 1.86，发现性研究中p = 1.07×10，重复性研究中p = 0.03，荟萃分析中p = 9.53×10]。……参与神经元分化。……参与内体循环，与乳腺癌有关。注释为……的rs587936变异体与生存时间延长有关[HR……，95% CI - 0.83，发现性研究中p = 4.79×10，重复性研究中p = 0.02，荟萃分析中p = 2.25×10]。……是一种ras/GAP肿瘤抑制基因，在血管组织中高度表达。……有多项证据表明其可预防动脉粥样硬化。
重复性研究结果确定了两个候选基因，可进一步研究其与高危CAD患者生存的关联：新位点……（rs13007553）和具有生物学相关性的候选基因……（rs587936）。这些候选基因与已验证的长寿候选基因不重叠。未来的研究可以进一步确定常见变异在CAD患者生存结果中的作用，并最终改善这些患者的纵向预后。
