Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, H/12, Islamabad, Pakistan.
Department of Pathology, Children's Hospital & The Institute of Child Health Multan, Pakistan.
Dis Markers. 2020 Jun 27;2020:9738567. doi: 10.1155/2020/9738567. eCollection 2020.
Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (≥70%) and mild/minimal stenosis (<30%). Five SNPs demonstrated significant associations: three with additive genetic models /rs4252120 ( = 0.0078), /rs2505083 ( = 0.005), and /rs2048327 ( = 0.045) and two with recessive models /rs602633 ( = 0.005) and /rs46522 ( = 0.03). /rs4252120 was in LD with two functional variants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise, /rs2505083 was in LD with a functional SNP, /rs3739998, having a RegulomeDB score of 2b. In the GTEx database, /rs2505083, /rs2048327, /rs602633, and /rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD.
全基因组关联研究（GWAS）已经揭示了多个与冠心病（CAD）相关的遗传风险位点。我们评估了 43 个 CAD 位点的 47 个全基因组显著单核苷酸多态性（SNP）与巴基斯坦样本中 663 例临床确诊和血管造影证实的冠心病患者冠状动脉狭窄的相关性。使用 iPLEX Gold 技术确定基因型。所有统计分析均使用 R 软件进行。使用 SNAP 网络门户确定显著 SNP 之间的连锁不平衡（LD），并使用 RegulomeDB 和基因型组织表达（GTEx）数据库对 SNP 进行功能注释。对严重狭窄（≥70%）和轻度/最小狭窄（<30%）患者进行基因分型比较。有 5 个 SNP 表现出显著相关性：三个 SNP 采用加性遗传模型，rs4252120（ = 0.0078）、rs2505083（ = 0.005）和 rs2048327（ = 0.045），两个 SNP 采用隐性遗传模型 rs602633（ = 0.005）和 rs46522（ = 0.03）。rs4252120 与两个功能变异体 rs4252126 和 rs4252135 存在连锁不平衡，每个变异体的 RegulomeDB 评分为 1f。同样，rs2505083 与功能 SNP rs3739998 存在连锁不平衡，RegulomeDB 评分为 2b。在 GTEx 数据库中，rs2505083、rs2048327、rs602633 和 rs46522 SNP 被发现是 CAD 相关组织中的表达数量性状基因座（eQTLs）。总之，先前在欧洲 GWAS 中报道的 5 个全基因组显著 SNP 在巴基斯坦样本中得到了复制。需要对更大的非欧洲人群进行进一步的关联研究，以了解 CAD 的全球遗传结构。
