家族性高胆固醇血症（FH）是常见单基因遗传病，因高冠心病风险受国际高度关注。研究发现LDL受体等3种FH致病基因突变仅能解释30%患者，其余患者病因不明。新近报道，脂代谢相关多个微效基因协同作用也参与FH发病；我们前期在国家自然基金资助下构建了脂代谢相关95个基因外显子捕获芯片，在未检测到致病突变的FH患者中检测到大量SNP，其中12个频率较高，但它们是否是FH关键基因位点、并通过协同作用影响胆固醇代谢有待研究。我们提出"FH发病除单基因致病机制外，可能还存在多基因协同作用机制"的假说。拟收集北方汉族FH核心家系，利用外显子芯片进行基因分型；生物信息学预测12个SNP功能；以肝细胞为模型,采用单点和双点诱变、单转染和共转染及基因沉默技术，分别观察12个SNP及组合所编码变异蛋白对LDL受体功能和胆固醇代谢的影响；在未发现突变的患者中检测12个SNP；验证假说。本项目对FH早期诊断意义重大。

Familial hypercholesterlolemia (FH) is a autosomal dominant disorder, the higher rate of premature coronary heart disease has been concerned by the world. But our country still have not enough attention. With standard molecular diagnostic techniques, a familial hypercholesterolaemia-causing mutation can be detected only in 30% of patients with FH. Recent researches have showed a substantial polygenic contribution might add to the variable penetrance of FH. We performed target exome sequencing of 95 genes by previous National Natural Science Foundation and detected a great number of single nucleotide polymorphism (SNP).We found 12 high frequency of SNP, but it is not clear that how to dig out the key locations from a FH and whether these SNPs affect cholesterol metabolism andinteraction? We hypothesized that "In addition to the monogenic mechanisms in FH subjects, there may also exist polygenic co-effect". This project will first study the Northern Han FH nuclear family by a larger sample, use the target exome sequencing chip to array genotype; use bioinformatics method to predict the 12 SNPs influence on cholesterol metabolism; use the single-point mutation and two-point mutation, single transfection and co-transfection and siRNA to specify the SNPs; observe the effect of variation of protein on LDL receptor function and cholesterol metabolism; enlarge the sample detection of 12 SNP in undetected mutations in patients with FH to verify our hypothesis. This is important for the early diagnosis of FH.