Coutinho Maria Francisca, Bourbon Mafalda, Prata Maria João, Alves Sandra
Grupo de Investigação em Doenças Lisossomais de Sobrecarga, Unidade de I&D; Departamento de Genética Humana, INSA, Porto, Portugal; IPATIMUP, Porto, Portugal; Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal.
Rev Port Cardiol. 2013 Oct;32(10):793-9. doi: 10.1016/j.repc.2013.02.006. Epub 2013 Jul 31.
Plasma low-density lipoprotein cholesterol (LDL-C) levels are a key determinant of the risk of cardiovascular disease, which is why many studies have attempted to elucidate the pathways that regulate its metabolism. Novel latest-generation sequencing techniques have identified a strong association between the 1p13 locus and the risk of cardiovascular disease caused by changes in plasma LDL-C levels. As expected for a complex phenotype, the effects of variation in this locus are only moderate. Even so, knowledge of the association is of major importance, since it has unveiled a new metabolic pathway regulating plasma cholesterol levels. Crucial to this discovery was the work of three independent teams seeking to clarify the biological basis of this association, who succeeded in proving that SORT1, encoding sortilin, was the gene in the 1p13 locus involved in LDL metabolism. SORT1 was the first gene identified as determining plasma LDL levels to be mechanistically evaluated and, although the three teams used different, though appropriate, experimental methods, their results were in some ways contradictory. Here we review all the experiments that led to the identification of the new pathway connecting sortilin with plasma LDL levels and risk of myocardial infarction. The regulatory mechanism underlying this association remains unclear, but its discovery has paved the way for considering previously unsuspected therapeutic targets and approaches.
血浆低密度脂蛋白胆固醇（LDL-C）水平是心血管疾病风险的关键决定因素，这就是为什么许多研究试图阐明调节其代谢的途径。新型的最新一代测序技术已经确定了1p13基因座与血浆LDL-C水平变化导致的心血管疾病风险之间的紧密关联。正如对复杂表型的预期那样，该基因座变异的影响仅为中等程度。即便如此，对这种关联的了解至关重要，因为它揭示了一条调节血浆胆固醇水平的新代谢途径。这一发现的关键在于三个独立团队的工作，他们试图阐明这种关联的生物学基础，并成功证明编码sortilin的SORT1是1p13基因座中参与LDL代谢的基因。SORT1是第一个被确定为决定血浆LDL水平且经过机制评估的基因，尽管这三个团队使用了不同但合适的实验方法，但其结果在某些方面相互矛盾。在此，我们回顾了所有导致确定sortilin与血浆LDL水平及心肌梗死风险之间新途径的实验。这种关联背后的调节机制仍不清楚，但其发现为考虑以前未被怀疑的治疗靶点和方法铺平了道路。
