1 Research Institute of the McGill University Health Centre, Royal Victoria Hospital, Montreal, Canada.
2 Faculty of Medicine, University of Toronto, Canada.
Eur J Prev Cardiol. 2019 Aug;26(12):1262-1270. doi: 10.1177/2047487319829746. Epub 2019 Feb 12.
AIMS: Familial hypercholesterolemia (FH) is the most common genetic disorder in medicine, with a prevalence of 1/250. Affected individuals have elevated low-density lipoprotein cholesterol (LDL-C) and an increased lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The diagnosis of FH is based on algorithms that include LDL-C levels, physical manifestations, family history of high LDL-C and premature ASCVD, and, more recently, genetic testing. We sought to determine the impact of genetic testing on the: 1) diagnosis of 'definite familial hypercholesterolemia', 2) initiation and adherence of lipid-lowering therapy and 3) risk of ASCVD. METHODS: We performed a systematic review and meta-analysis, pooling odds ratios and 95% confidence intervals for ASCVD from studies comparing risk estimates in individuals harboring FH-causing variants and unaffected individuals. RESULTS: After screening 3304 unique publications, 56 studies were included in the analysis. 1) Genetic testing provided confirmation of FH in 28-80%, over clinical criteria alone, depending on the diagnostic algorithm and the method of analysis. In two large population-based studies comprising 76,751 individuals, an FH-causing variant was identified in only 1.7-2.5% of subjects with an LDL-C > 4.9 mmol/L (190 mg/dL). 2) A confirmed molecular diagnosis increased lipid-lowering therapy adherence (five studies, = 4181 definite FH). 3) Loss-of-function variant of the were at a markedly increased risk of myocardial infarction (odds ratio 6.77, 95% confidence interval 4.75-9.66), and patients with a milder (hypomorphic) pathogenic change had a 4.4-fold increase in risk (odds ratio 4.4, 95% confidence interval 2.34-8.26), compared with controls. CONCLUSION: DNA sequencing confirms the diagnosis of FH but has a poor yield in unselected patients whose sole criterion is an elevated LDL-C. Initiation and adherence to treatment is improved. The risk of ASCVD is 4.4- to 6.8-fold increased in patients with an FH-causing variant compared with controls, depending on the severity of the DNA change.
目的：家族性高胆固醇血症（FH）是医学中最常见的遗传性疾病，患病率为 1/250。受影响的个体低密度脂蛋白胆固醇（LDL-C）升高，终生患动脉粥样硬化性心血管疾病（ASCVD）的风险增加。FH 的诊断基于包括 LDL-C 水平、身体表现、家族性高 LDL-C 和早发 ASCVD 病史以及最近的基因检测在内的算法。我们旨在确定基因检测对以下方面的影响：1）“明确家族性高胆固醇血症”的诊断，2）降脂治疗的启动和依从性，以及 3）ASCVD 的风险。
方法：我们进行了系统评价和荟萃分析，汇总了比较携带 FH 致病变异个体和未受影响个体风险估计的研究中 ASCVD 的比值比和 95%置信区间。
结果：在筛选了 3304 篇独特的文献后，有 56 项研究纳入了分析。1）基因检测在仅基于临床标准的情况下，提供了 FH 的确认，其比例为 28-80%，具体取决于诊断算法和分析方法。在两项包含 76751 名个体的大型基于人群的研究中，只有 1.7-2.5% 的 LDL-C>4.9mmol/L（190mg/dL）的个体中发现了 FH 致病变异。2）明确的分子诊断增加了降脂治疗的依从性（五项研究，共 4181 例明确的 FH）。3）载脂蛋白 B 基因的功能丧失性变异与心肌梗死的风险显著增加（比值比 6.77，95%置信区间 4.75-9.66），与对照组相比，载脂蛋白 B 基因轻度（功能减弱型）致病性变异患者的风险增加 4.4 倍（比值比 4.4，95%置信区间 2.34-8.26）。
结论：DNA 测序可确认 FH 的诊断，但在仅以 LDL-C 升高为唯一标准的未选择患者中，其检出率较低。治疗的启动和依从性得到改善。与对照组相比，患有 FH 致病变异的患者的 ASCVD 风险增加 4.4-6.8 倍，具体取决于 DNA 变化的严重程度。
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