Background

Familial hypercholesterolemia (FH) is a common inherited disease characterized by elevated low-density lipoprotein cholesterol (LDL-C) plasma levels and increased cardiovascular disease risk. Most patients carry a mutation in the low-density lipoprotein receptor gene (LDLR). Common and rare variants in the genes encoding adenosine triphosphate–binding cassette transporters G5 and G8 (ABCG5 and ABCG8) have been shown to affect LDL-C levels.

Objective

The objective of this study was to investigate whether and to which extent heterozygous variants in ABCG5 and ABCG8 are associated with the hypercholesterolemic phenotype.

Methods

We sequenced ABCG5 and ABCG8 in a cohort of 3031 clinical FH patients and compared the prevalence of variants with a European reference population (gnomAD). Clinical characteristics of carriers of putative pathogenic variants in ABCG5 and/or ABCG8 were compared with heterozygous carriers of mutations in LDLR. Furthermore, we assessed the segregation of one ABCG5 and two ABCG8 variants with plasma lipid and sterol levels in three kindreds.

Results

The frequencies of (likely) pathogenic LDLR, APOB, PCSK9, ABCG5, and ABCG8 variants in our FH cohort were 11.42%, 2.84%, 0.69%, 1.48%, and 0.96%, respectively. We identified 191 ABCG5 and ABCG8 variants of which 53 were classified as pathogenic or likely pathogenic. Of these 53 variants, 51 were either absent from a reference population or more prevalent in our FH cohort than in the reference population. LDL-C levels were significantly lower in heterozygous carriers of a (likely) pathogenic ABCG5 or ABCG8 variant compared to LDLR mutation carriers (6.2 ± 1.7 vs 7.2 ± 1.7 mmol/L, P < .001). The combination of both an ABCG5 or ABCG8 variant and a LDLR variant was found not to be associated with significant higher LDL-C levels (7.8 ± 2.3 vs 7.2 ± 1.7 mmol/L, P = .259). Segregation analysis in three families (nine carriers, in addition to the index cases, and 16 noncarriers) did not show complete segregation of the ABCG5/G8 variants with high LDL-C levels, and LDL-C levels were not different (3.9 ± 1.3 vs 3.5 ± 0.6 mmol/L in carriers and noncarriers, respectively, P = .295), while plasma plant sterol levels were higher in carriers compared to noncarriers (cholestanol: 10.2 ± 1.7 vs 8.4 ± 1.6 μmol/L, P = .007; campesterol: 22.5 ± 10.1 vs 13.4 ± 3.5 μmol/L, P = .008; sitosterol: 17.0 ± 11.6 vs 8.2 ± 2.6 μmol/L, P = .024).

Conclusions

2.4% of subjects in our FH cohort carried putative pathogenic ABCG5 and ABCG8 variants but had lower LDL-C levels compared to FH patients who were heterozygous carriers of an LDLR variant. These results suggest a role for these genes in hypercholesterolemia in FH patients with less severely elevated LDL-C levels. We did not find evidence that these variants cause autosomal dominant FH.

中文翻译：

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家族性高胆固醇血症的ABCG5和ABCG8遗传变异。

背景

家族性高胆固醇血症（FH）是一种常见的遗传性疾病，其特征在于低密度脂蛋白胆固醇（LDL-C）血浆水平升高和心血管疾病风险增加。大多数患者携带低密度脂蛋白受体基因（LDLR）突变。编码三磷酸腺苷结合盒转运蛋白G5和G8（ABCG5和ABCG8）的基因的常见和稀有变体影响LDL-C水平。

目的

这项研究的目的是调查ABCG5和ABCG8中的杂合变异体与高胆固醇血症表型是否相关以及在多大程度上相关。

方法

我们在3031名临床FH患者队列中对ABCG5和ABCG8进行了测序，并将变体的患病率与欧洲参考人群（gnomAD）进行了比较。比较了ABCG5和/或ABCG8的假定致病变异携带者与LDLR突变的杂合子携带者的临床特征。此外，我们评估了三种血脂中一种ABCG5和两种ABCG8变体与血浆脂质和固醇水平的分离。

结果

在我们的FH队列中，（可能）致病性LDLR，APOB，PCSK9，ABCG5和ABCG8变异的频率分别为11.42％，2.84％，0.69％，1.48％和0.96％。我们确定了191个ABCG5和ABCG8变体，其中53个被分类为致病性或可能致病性。在这53个变体中，参考人群中不存在51个，或者在我们的FH队列中比参考人群中更普遍。与（可能的）致病性ABCG5或ABCG8变体的杂合子携带者相比，LDL-C水平显着低于LDLR突变携带者（6.2±1.7对7.2±1.7 mmol / L，P  <.001）。两者的结合发现ABCG5或ABCG8变体和LDLR变体与较高的LDL-C水平无关（7.8±2.3 vs 7.2±1.7 mmol / L，P  = .259）。在三个家族中（9个携带者，除索引病例外，还有16个非携带者）进行的分离分析未显示出具有高LDL-C水平的ABCG5 / G8变体的完全分离，LDL-C水平没有差异（3.9±1.3）分别与载体和非载体中的3.5±0.6 mmol / L相比，P  = .295），而载体中血浆植物固醇水平高于非载体（胆固醇：10.2±1.7 vs 8.4±1.6μmol/ L，P  = .007） ;菜油甾醇：22.5±10.1和13.4±3.5μmol/ L，P = .008; 谷固醇：17.0±11.6 vs 8.2±  2.6μmol / L，P = 0.024）。

结论

在我们的FH队列科目2.4％进行推测致病ABCG5和ABCG8变种但相比FH谁是病人的杂合子携带者具有较低的LDL-C水平LDLR的变体。这些结果表明这些基因在LDL-C水平升高不那么严重的FH患者中在高胆固醇血症中起作用。我们没有发现证据表明这些变体会导致常染色体显性FH。