DataSheet1_Implementation of a biochemical, clinical, and genetic screening programme for familial hypercholesterolemia in 26 centres in Spain: The ARIAN study.DOCX

Background: Familial hypercholesterolemia (FH) is clearly underdiagnosed and undertreated. The aim of this present study is to assess the benefits of FH screening through a joint national program implemented between clinical laboratories and lipid units.Methods: All clinical laboratory tests from 1 January 2017 to 31 December 2018 were reviewed, and those with LDL cholesterol (LDL-C) levels >250 mg/dl were identified in subjects >18 years of age of both sexes. Once secondary causes had been ruled out, the treating physician was contacted and advised to refer the patient to an LU to perform the Dutch Lipid Clinic Network score and to request genetic testing if the score was ≥6 points. Next Generation Sequencing was used to analyse the promoter and coding DNA sequences of four genes associated with FH (LDLR, APOB, PCSK9, APOE) and two genes that have a clinical overlap with FH characteristics (LDLRAP1 and LIPA). A polygenic risk score based on 12 variants was also obtained.Results: Of the 3,827,513 patients analyzed in 26 centers, 6,765 had LDL-C levels >250 mg/dl. Having ruled out secondary causes and known cases of FH, 3,015 subjects were included, although only 1,205 treating physicians could be contacted. 635 patients were referred to an LU and genetic testing was requested for 153 of them. This resulted in a finding of sixty-seven pathogenic variants for FH, 66 in the LDLR gene and one in APOB. The polygenic risk score was found higher in those who had no pathogenic variant compared to those with a pathogenic variant.Conclusion: Despite its limitations, systematic collaboration between clinical laboratories and lipid units allows for the identification of large numbers of patients with a phenotypic or genetic diagnosis of FH, which will reduce their vascular risk. This activity should be part of the clinical routine.

背景：家族性高胆固醇血症（FH）的确诊与治疗存在明显的不足。本研究的目的是评估通过临床实验室与血脂单位联合实施的全国性项目进行FH筛查的益处。方法：回顾了2017年1月1日至2018年12月31日期间所有临床实验室检测数据，并在18岁以上的男女受试者中识别出低密度脂蛋白胆固醇（LDL-C）水平大于250 mg/dl的个体。在排除继发原因后，联系治疗医师，建议将患者转诊至血脂单位进行荷兰血脂临床网络评分，若评分≥6分，则建议进行基因检测。利用下一代测序技术分析了与FH相关的四个基因（LDLR、APOB、PCSK9、APOE）及其与FH特征具有临床重叠的基因（LDLRAP1和LIPA）的启动子和编码DNA序列。此外，还获得了基于12个位点的多基因风险评分。结果：在26个中心分析的3827513名患者中，有6765名患者的LDL-C水平大于250 mg/dl。在排除继发原因和已知FH病例后，共有3015名受试者被纳入研究，尽管只有1205名治疗医师能够被联系。635名患者被转诊至血脂单位，其中153名患者进行了基因检测。这导致在67名FH患者中发现了致病性变异，其中66例位于LDLR基因，1例位于APOB基因。与具有致病性变异的患者相比，无致病性变异的患者多基因风险评分更高。结论：尽管存在局限性，但临床实验室与血脂单位之间的系统性合作有助于识别大量具有表型或遗传学诊断的FH患者，这将降低他们的血管风险。此类活动应成为临床常规的一部分。