Dungan Jennifer R, Qin Xue, Gregory Simon G, Cooper-Dehoff Rhonda, Duarte Julio D, Qin Huaizhen, Gulati Martha, Taylor Jacquelyn Y, Pepine Carl J, Hauser Elizabeth R, Kraus William E
Division of Healthcare in Adult Populations, School of Nursing, Duke University, Durham, NC 27710, USA.
Division of Cardiovascular Medicine, Department of Cardiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Am Heart J Plus. 2022 May;17. doi: 10.1016/j.ahjo.2022.100152. Epub 2022 Jun 14.
Ischemic coronary heart disease (IHD) is the leading cause of death worldwide. Genetic variation is presumed to be a major factor underlying sex differences for IHD events, including mortality. The purpose of this study was to identify sex-specific candidate genes associated with all-cause mortality among people diagnosed with coronary artery disease (CAD).
We performed a sex-stratified, exploratory genome-wide association (GWAS) screen using existing data from CAD-diagnosed males ( = 510) and females ( = 174) who reported European ancestry from the Duke Catheterization Genetics biorepository. Extant genotype data for 785,945 autosomal SNPs generated with the Human Omni1-Quad BeadChip (Illumina, CA, USA) were analyzed using an additive inheritance model. We estimated instantaneous risk of all-cause mortality by genotype groups across the 11-year follow-up using Cox multivariate regression, covarying for age and genomic ancestry.
The top GWAS hits associated with all-cause mortality among people with CAD included 8 SNPs among males and 15 among females ( = 1 × 10 or 10), adjusted for covariates. Cross-sex comparisons revealed distinct candidate genes. Biologically relevant candidates included rs9932462 ( and rs2835913 ( among males and rs7217169 (), rs8021816 (), rs8133010 (), and rs12145981 () among females.
We report 20 sex-specific candidate genes having suggestive association with all-cause mortality among CAD-diagnosed subjects. Findings demonstrate proof of principle for identifying sex-associated genetic factors that may help explain differential mortality risk in people with CAD. Replication and meta-analyses in larger studies with more diverse samples will strengthen future work in this area.
缺血性冠心病（IHD）是全球主要的死亡原因。遗传变异被认为是IHD事件（包括死亡率）性别差异的主要潜在因素。本研究的目的是确定与冠状动脉疾病（CAD）诊断患者全因死亡率相关的性别特异性候选基因。
我们使用来自杜克导管插入遗传学生物样本库的现有数据，对诊断为CAD的男性（n = 510）和女性（n = 174）进行了性别分层的探索性全基因组关联（GWAS）筛查，这些参与者均报告有欧洲血统。使用人类全基因组Omni1-Quad BeadChip（美国加利福尼亚州Illumina公司）生成的785,945个常染色体单核苷酸多态性（SNP）的现有基因型数据，采用加性遗传模型进行分析。我们使用Cox多变量回归估计了在11年随访期间各基因型组的全因死亡率瞬时风险，并对年龄和基因组血统进行了协变量调整。
在调整协变量后，与CAD患者全因死亡率相关的GWAS最显著位点在男性中有8个SNP，在女性中有15个SNP（P = 1×10⁻⁸或更低）。跨性别比较揭示了不同的候选基因。生物学上相关的候选基因在男性中包括rs9932462（P = 4.4×10⁻⁹）和rs2835913（P = 3.2×10⁻⁸），在女性中包括rs7217169（P = 2.1×10⁻⁸）、rs8021816（P = 3.4×10⁻⁸）、rs8133010（P = 3.8×10⁻⁸）和rs12145981（P = 7.7×10⁻⁹）。
我们报告了20个与CAD诊断患者全因死亡率有提示性关联的性别特异性候选基因。研究结果证明了识别可能有助于解释CAD患者不同死亡风险的性别相关遗传因素的原理。在更多样化样本的更大规模研究中进行重复验证和荟萃分析将加强该领域未来的工作。
