Talmud Philippa J, Futema Marta, Humphries Steve E
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
Curr Opin Lipidol. 2014 Aug;25(4):274-81. doi: 10.1097/MOL.0000000000000090.
Genome-Wide Association Studies have provided robust identification of approximately 100 genetic loci determining plasma lipid parameters. Using these multiple common genetic lipid-determining variants in a 'gene score' has thrown new light on the mode of inheritance of familial lipid disorders.
Different hypertriglyceridaemia states have been explained by the polygenic coinheritance of triglyceride-raising alleles. Taking this gene score approach with 12 LDL-cholesterol-raising alleles, we reported that for patients with a clinical diagnosis of familial hypercholesterolaemia, but no identified rare mutation in the familial hypercholesterolaemia-causing genes, LDL receptor, apolipoprotein B and PCSK9, the most likely explanation for their elevated LDL-C levels was a polygenic, not a monogenic, cause of the disease.
These findings have wider implications for understanding complex disorders, and may very well explain the genetic basis of familial combined hyperlipidaemia, another familial lipid disorder in which the genetic cause(s) has remained elusive.
全基因组关联研究已有力地鉴定出约100个决定血浆脂质参数的基因位点。在“基因评分”中使用这些多个常见的决定脂质的基因变异，为家族性脂质紊乱的遗传模式带来了新的认识。
不同的高甘油三酯血症状态已通过升高甘油三酯等位基因的多基因共同遗传得到解释。采用这种基因评分方法，纳入12个升高低密度脂蛋白胆固醇的等位基因，我们报告称，对于临床诊断为家族性高胆固醇血症，但在家族性高胆固醇血症致病基因、低密度脂蛋白受体、载脂蛋白B和前蛋白转化酶枯草溶菌素9中未发现罕见突变的患者，其低密度脂蛋白胆固醇水平升高的最可能原因是多基因而非单基因导致的疾病。
这些发现对于理解复杂疾病具有更广泛的意义，并且很可能解释家族性混合性高脂血症的遗传基础，家族性混合性高脂血症是另一种遗传病因仍不清楚的家族性脂质紊乱。
