与临床诊断为家族性高胆固醇血症的家族中多基因高胆固醇血症相关的单核苷酸变异

Single Nucleotide Variants Associated With Polygenic Hypercholesterolemia in Families Diagnosed Clinically With Familial Hypercholesterolemia.

作者信息

Lamiquiz-Moneo Itziar, Pérez-Ruiz María Rosario, Jarauta Estíbaliz, Tejedor María Teresa, Bea Ana M, Mateo-Gallego Rocío, Pérez-Calahorra Sofía, Baila-Rueda Lucía, Marco-Benedí Victoria, de Castro-Orós Isabel, Cenarro Ana, Civeira Fernando

机构信息

Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBERCV, Universidad de Zaragoza, Zaragoza, Spain.

出版信息

Rev Esp Cardiol (Engl Ed). 2018 May;71(5):351-356. doi: 10.1016/j.rec.2017.07.010. Epub 2017 Sep 14.

DOI:10.1016/j.rec.2017.07.010

PMID:28919240

Abstract

INTRODUCTION AND OBJECTIVES

Approximately 20% to 40% of clinically defined familial hypercholesterolemia cases do not show a causative mutation in candidate genes, and some of them may have a polygenic origin. A cholesterol gene risk score for the diagnosis of polygenic hypercholesterolemia has been demonstrated to be valuable to differentiate polygenic and monogenic hypercholesterolemia. The aim of this study was to determine the contribution to low-density lipoprotein cholesterol (LDL-C) of the single nucleotide variants associated with polygenic hypercholesterolemia in probands with genetic hypercholesterolemia without mutations in candidate genes (nonfamilial hypercholesterolemia genetic hypercholesterolemia) and the genetic score in cascade screening in their family members.

METHODS

We recruited 49 nonfamilial hypercholesterolemia genetic hypercholesterolemia families (294 participants) and calculated cholesterol gene scores, derived from single nucleotide variants in SORT1, APOB, ABCG8, APOE and LDLR and lipoprotein(a) plasma concentration.

RESULTS

Risk alleles in SORT1, ABCG8, APOE, and LDLR showed a statistically significantly higher frequency in blood relatives than in the 1000 Genomes Project. However, there were no differences between affected and nonaffected members. The contribution of the cholesterol gene score to LDL-C was significantly higher in affected than in nonaffected participants (P = .048). The percentage of the LDL-C variation explained by the score was 3.1%, and this percentage increased to 6.9% in those families with the highest genetic score in the proband.

CONCLUSIONS

Nonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C. Their contribution varies greatly among families, indicating the complexity and heterogeneity of these forms of hypercholesterolemias. The gene score explains a small percentage of LDL-C, which limits its use in diagnosis.

摘要

引言与目的

临床定义的家族性高胆固醇血症病例中，约20%至40%在候选基因中未显示致病突变，其中一些可能具有多基因起源。已证明用于诊断多基因高胆固醇血症的胆固醇基因风险评分对于区分多基因和单基因高胆固醇血症具有重要价值。本研究的目的是确定与多基因高胆固醇血症相关的单核苷酸变异对候选基因无突变的遗传性高胆固醇血症先证者（非家族性高胆固醇血症遗传性高胆固醇血症）低密度脂蛋白胆固醇（LDL-C）的贡献，以及其家庭成员级联筛查中的基因评分。

方法

我们招募了49个非家族性高胆固醇血症遗传性高胆固醇血症家庭（294名参与者），并计算了胆固醇基因评分，该评分源自SORT1、APOB、ABCG8、APOE和LDLR中的单核苷酸变异以及血浆脂蛋白(a)浓度。

结果

SORT1、ABCG8、APOE和LDLR中的风险等位基因在血亲中的频率在统计学上显著高于千人基因组计划中的频率。然而，患病成员和未患病成员之间没有差异。胆固醇基因评分对LDL-C的贡献在患病参与者中显著高于未患病参与者（P = 0.048）。评分所解释的LDL-C变异百分比为3.1%，在先证者基因评分最高的那些家庭中，这一百分比增加到6.9%。