Department of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Department of Medical Laboratory, Henan Provincial Chest Hospital, Zhengzhou 450008, China.
Gene. 2022 May 20;823:146343. doi: 10.1016/j.gene.2022.146343. Epub 2022 Feb 24.
ATP binding cassette transporters ABCA1 and ABCG1 play a crucial role in cholesterol efflux and reverse cholesterol transport (RCT), thereby rendering ischemic stroke (IS) susceptibility. Variants of ABCA1/G1 have been implicated in etiology of IS. This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of ABCA1/G1 with plasma lipid variability and the risk of IS in Chinese Han Population.
Totally 249 IS patients and 226 healthy controls were enrolled and 10 SNPs of ABCA1/G1 were screened for genotyping by kompetitive allele-specific polymerase chain reaction (KASP) and validated by sanger sequencing. The logistic regression analysis was performed to identify risk alleles of IS and appropriate genetic model. The genetic risk scores (GRS) and predicted risks for all individuals was computed. Based on different plasma lipid levels, we applied stratified analyses for subgroups. Linkage disequilibrium (LD) test was used to explore different functional haplotype combinations. Association between specific allele or genotype of the SNPs of ABCA1/G1 and plasma lipid or lipoproteins levels were also investigated.
Besides total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), significant differences of clinical data were observed between IS and control group. The rare GG genotype frequencies of rs4149338 on ABCA1 was higher in IS patients than those in controls (11.4%, 4.6%, respectively, P = 0.037). Frequencies of rs57137919 on ABCG1 for rare AA genotype was lower in IS group than those in control group (4.6%, 13.3%, respectively, P = 0.030). GRS showed ability to discriminate IS patients and controls (AUC = 0.633, P < 0.001). Haplotype A-A (rs4149339-rs4149338) was correlated with reduced risk of IS (P = 0.023). Association analysis showed that subjects with rare AA genotype of rs57137919 had the lowest LDL-C levels while rare GG genotype of rs4149338 had lower TC level than those with AA genotype. The mRNA expression of ABCG1 was higher in IS patients, especially in the patients with frequent GG genotype of rs57137919, and was positively correlated with higher ABCG1 expression level and plasma LDL-C level.
Polymorphisms of ABCA1/G1 associated with varieties of plasma lipid levels and risk of IS.
ATP 结合盒转运蛋白 ABCA1 和 ABCG1 在胆固醇外排和胆固醇逆转运（RCT）中发挥关键作用，从而使缺血性中风（IS）易感性。ABCA1/G1 的变体与 IS 的病因有关。本研究旨在探讨中国汉族人群中 ABCA1/G1 单核苷酸多态性（SNP）与血浆脂质变异性和 IS 风险的关系。
共纳入 249 例 IS 患者和 226 例健康对照者，采用竞争性等位基因特异性聚合酶链反应（KASP）筛选 ABCA1/G1 的 10 个 SNP 进行基因分型，并通过 Sanger 测序进行验证。采用 logistic 回归分析鉴定 IS 的风险等位基因和合适的遗传模型。计算所有个体的遗传风险评分（GRS）和预测风险。根据不同的血浆脂质水平，我们进行了亚组分层分析。采用连锁不平衡（LD）检验探讨不同功能单倍型组合。还研究了 ABCA1/G1 的 SNP 特定等位基因或基因型与血浆脂质或脂蛋白水平之间的关系。
除总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）外，IS 组和对照组之间的临床数据差异有统计学意义。ABCA1 上 rs4149338 的罕见 GG 基因型频率在 IS 患者中高于对照组（分别为 11.4%和 4.6%，P=0.037）。ABCG1 上 rs57137919 的罕见 AA 基因型频率在 IS 组中低于对照组（分别为 4.6%和 13.3%，P=0.030）。GRS 能够区分 IS 患者和对照组（AUC=0.633，P<0.001）。单倍型 A-A（rs4149339-rs4149338）与 IS 风险降低相关（P=0.023）。关联分析显示，rs57137919 罕见 AA 基因型的受试者 LDL-C 水平最低，而 rs4149338 罕见 GG 基因型的 TC 水平低于 AA 基因型。IS 患者的 ABCG1 mRNA 表达水平较高，尤其是 rs57137919 频繁 GG 基因型的患者，且与 ABCG1 表达水平和血浆 LDL-C 水平呈正相关。
ABCA1/G1 的多态性与多种血浆脂质水平和 IS 风险相关。
