Hubacek J A, Adamkova V, Lanska V, Dlouha D
Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Physiol Res. 2017 Apr 5;66(Suppl 1):S101-S111. doi: 10.33549/physiolres.933580.
Since 2007, the year of their first widespread use, genome-wide association studies (GWAS) have become the "gold standard" for the detection of causal genes and polymorphisms in all fields of human medicine. Cardiovascular disease (CVD), one of the major causes of morbidity and mortality, is no exception. The first GWAS focused on hypercholesterolemia and dyslipidemia as the major CVD determinants. GWAS confirm the importance of most of the previously identified genes (e.g. APOE, APOB, LDL-R) and recognize the importance of new genetic determinants (e.g. within the CILP2 or SORT1 gene clusters). Nevertheless, the results of GWAS still require confirmation by independent studies, as interethnic and interpopulation variability of SNP effects have been reported. We analyzed an association between eight variants within seven through GWAs detected loci and plasma lipid values in the Czech post-MONICA population sample (N=2,559). We confirmed an association (all P<0.01) between plasma LDL-cholesterol values and variants within the CILP2 (rs16996148), SORT1 (rs646776), APOB (rs693), APOE (rs4420638) and LDL-R (rs6511720) genes in both males (N=1,194) and females (N=1,368). In contrast, variants within the APOB (rs515135), PCSK9 (rs11206510) and HMGCoAR (rs12654264) genes did not significantly affect plasma lipid values in Czech males or females. Unweighted gene score values were linearly associated with LDL-cholesterol values both in males (P<0.0005) and females (P<0.00005). We confirmed the effects of some, but not all analyzed SNPs on LDL-cholesterol levels, reinforcing the necessity for replication studies of GWA-detected gene variants.
自2007年首次广泛应用以来，全基因组关联研究（GWAS）已成为人类医学各个领域检测因果基因和多态性的“金标准”。心血管疾病（CVD）作为发病和死亡的主要原因之一，也不例外。首个GWAS聚焦于高胆固醇血症和血脂异常作为主要的心血管疾病决定因素。GWAS证实了大多数先前确定的基因（如APOE、APOB、LDL-R）的重要性，并认识到新的遗传决定因素（如在CILP2或SORT1基因簇内）的重要性。然而，由于已报道SNP效应存在种族间和群体间变异性，GWAS的结果仍需要独立研究予以证实。我们分析了捷克MONICA人群样本（N = 2559）中通过GWAS检测到的7个基因座内的8个变异与血脂值之间的关联。我们证实，在男性（N = 1194）和女性（N = 1368）中，血浆低密度脂蛋白胆固醇值与CILP2（rs16996148）、SORT1（rs646776）、APOB（rs693）、APOE（rs4420638）和LDL-R（rs6511720）基因内的变异之间存在关联（所有P<0.01）。相比之下，APOB（rs515135）、PCSK9（rs11206510）和HMGCoAR（rs12654264）基因内的变异对捷克男性或女性的血浆脂质值没有显著影响。未加权基因评分值与男性（P<0.0005）和女性（P<0.00005）的低密度脂蛋白胆固醇值呈线性相关。我们证实了部分（而非全部）分析的SNP对低密度脂蛋白胆固醇水平有影响，这进一步强调了对GWAS检测到的基因变异进行重复研究的必要性。
