Martín-Campos Jesús Maria
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IR-HSCSP)-Biomedical Research Institute Sant Pau (IIB-Sant Pau), C/Sant Quintí 77-79, 08041 Barcelona, Spain.
Biomedicines. 2021 Nov 19;9(11):1728. doi: 10.3390/biomedicines9111728.
Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene-gene and gene-environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.
血浆低密度脂蛋白胆固醇（LDL-c）水平的变化与发生某些常见和复杂疾病的高风险相关。LDL-c作为一种数量性状，是多因素的，取决于遗传和环境因素。在前基因组时代，靶向基因被用于检测高脂血症和低脂血症中的遗传因素，但这种方法仅解释了人群分布中的极端情况。随后，不太严重且最常见的血脂异常的遗传基础仍然未知。在基因组时代，对血浆LDL-c值极高的家族进行全外显子组测序鉴定出了一些新的候选基因，但这些基因不太可能解释大多数无法解释的病例。全基因组关联研究（GWAS）已经鉴定出了几个与血浆LDL-c相关的单核苷酸变异（SNV），引入了多基因起源的概念。开发了包括升高LDL-c的等位基因在内的多基因风险评分（PRS）来衡量小效应变异积累对血浆LDL-c的贡献。本文讨论了与LDL-c相关的无法解释的血脂异常的其他可能性，如镶嵌现象、母体效应和诱导的表观遗传变化。未来的研究应考虑基因-基因和基因-环境相互作用以及关于疾病驱动网络的综合信息的发展，包括表型、基因型、转录、蛋白质、代谢物和表观遗传学。
