GWAS of Statin response. Genome-wide association study of therapeutic response to statin drugs in cardiovascular disease

Cardiovascular disease (CVD) is one of the main causes of death in the world. The increased level of blood cholesterol is significantly correlated to CVD occurrence. Statins are a group of drugs that decrease the synthesis of cholesterol in the liver by inhibiting the final enzyme of the pathway named HMG-CoA reductase. Several investigations showed that different patients give different responses to the administration of these drugs according to their genetic background. In this research study, using Genome-Wide Association Studies (GWAS) data analysis methods, such as the SimpleM statistical approach and genomic connection matrix, we tried to discover the novel candidate SNPs that were involed in response to statin drugs. This investigation was carried out using 3,221 cardiovascular diseses patients data about genotypes and phenotypes of two important parameters, total cholesterol and LDL level, in response to statin administration. Functional annotation of nearest genes to candidate SNPs also was carried out by using comprehensive databases and tools such as BioMart-Ensembl, UCSC, NCBI, and WebGestalt software. Our results represented eight novel SNPs (rs10820084, rs4803750, rs10989887, rs1966503, rs17502794, rs10785232, rs484071, rs4785621) significantly associated with statin response in different individuals with cardiovascular disease for the first time. In addition, some groups of genes that are close to the SNPs were also represented and evaluated. Based on our results, some of these genes such as BAAT, BCL3, and CMTM6 have a direct functional impact on cholesterol level or LDL biosynthesis that confirmed the effects of nighbor SNPs on the response to statin drugs. Today, finding the genes and molecular mechanisms involved in the response to drugs is of great importance in personalized medicine.

心血管疾病（Cardiovascular disease, CVD）是全球主要致死病因之一。血液胆固醇水平升高与心血管疾病的发生存在显著相关性。他汀类药物是一类通过抑制胆固醇合成通路的末端酶——羟甲基戊二酰辅酶A还原酶（HMG-CoA reductase），降低肝脏内胆固醇合成的药物。多项研究表明，不同患者的遗传背景存在差异，因此对该类药物的给药响应也各不相同。本研究采用全基因组关联研究（Genome-Wide Association Studies, GWAS）数据分析方法，包括SimpleM统计方法与基因组连接矩阵，旨在挖掘与他汀类药物响应相关的新型候选单核苷酸多态性（SNPs）。本研究纳入3221名心血管疾病患者的基因分型与表型数据，分析其在接受他汀类药物给药后，总胆固醇与低密度脂蛋白胆固醇（Low-Density Lipoprotein, LDL）两项关键指标的变化情况。研究还通过BioMart-Ensembl、UCSC、NCBI及WebGestalt软件等综合数据库与工具，对候选单核苷酸多态性的临近基因进行功能注释。本研究首次筛选出8个与心血管疾病患者他汀类药物响应显著相关的新型单核苷酸多态性：rs10820084、rs4803750、rs10989887、rs1966503、rs17502794、rs10785232、rs484071及rs4785621。此外，本研究还对单核苷酸多态性临近的部分基因集进行了鉴定与评估。基于研究结果，BAAT、BCL3及CMTM6等部分基因对胆固醇水平或低密度脂蛋白胆固醇的生物合成具有直接调控功能，这验证了临近单核苷酸多态性对他汀类药物响应的影响。当前，挖掘药物响应相关的基因与分子机制，在个性化医疗领域具有重要意义。