Lange Leslie A, Willer Cristen J, Rich Stephen S
aUniversity of North Carolina, Chapel Hill, North Carolina bUniversity of Michigan, Ann Arbor, Michigan cUniversity of Virginia, Charlottesville, Virginia, USA.
Curr Opin Lipidol. 2015 Apr;26(2):96-102. doi: 10.1097/MOL.0000000000000159.
Genome-wide association scans (GWAS) have identified over 100 human loci associated with variation in lipids. The identification of novel genes and variants that affect lipid levels is made possible by next-generation sequencing, rare variant discovery and analytic advances. The current status of the genetic basis of lipid traits will be presented.
Expansion of GWAS sample sizes for lipid traits has not substantially increased the proportion of trait variance explained by common genetic variants (less than 15% of trait variation captured). Although GWAS has discovered novel loci and pathways with putative biological function and impact on cardiovascular disease risk, discovery of the genes in these loci remains challenging. Exome sequencing promises to identify genes with protein-coding variants with a large impact on lipids, as shown for LDL-cholesterol levels associated with novel (PNPLA5) and known (LDLR, PCSK9, APOB) genes.
Current results have increased our understanding of the genetic architecture of lipids, expanding the range of effect and frequency for variants identified for lipid traits. Identification of novel lipid-associated gene variants, even if small in effect or rare in the population, could provide important novel drug targets and biological pathways for dyslipidemia.
全基因组关联扫描（GWAS）已鉴定出100多个与脂质变异相关的人类基因座。新一代测序、罕见变异发现及分析进展使得鉴定影响脂质水平的新基因和变异成为可能。本文将介绍脂质性状遗传基础的现状。
脂质性状GWAS样本量的扩大并未显著增加常见遗传变异所解释的性状变异比例（捕获的性状变异不到15%）。尽管GWAS已发现具有假定生物学功能且对心血管疾病风险有影响的新基因座和途径，但确定这些基因座中的基因仍具有挑战性。外显子组测序有望鉴定出对脂质有重大影响的蛋白质编码变异基因，如与新基因（PNPLA5）和已知基因（LDLR、PCSK9、APOB）相关的低密度脂蛋白胆固醇水平所示。
目前的研究结果增进了我们对脂质遗传结构的理解，扩大了脂质性状所鉴定变异的效应范围和频率。鉴定新的脂质相关基因变异，即使其效应较小或在人群中罕见，也可能为血脂异常提供重要的新药物靶点和生物学途径。
