Theusch Elizabeth, Ting Flora Y, Qin Yuanyuan, Stevens Kristen, Naidoo Devesh, King Sarah M, Yang Neil, Orr Joseph, Han Brenda Y, Cyster Jason G, Chen Yii-Der I, Rotter Jerome I, Krauss Ronald M, Medina Marisa W
Department of Pediatrics, University of California San Francisco, Oakland, CA USA.
Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA USA.
bioRxiv. 2023 Jun 15:2023.06.14.544860. doi: 10.1101/2023.06.14.544860.
Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.
To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 μM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (), we followed up by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in (the mouse homolog of ).
The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 ( aka , rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 (, rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying allele(s) exhibited a significantly blunted LDL statin response.
Our and studies identified as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
他汀类药物可降低循环中的低密度脂蛋白胆固醇（LDLC）水平并降低心血管疾病风险。尽管总体上疗效显著，但他汀类药物疗效存在相当大的个体差异，其原因在很大程度上仍未得到解释。
为了鉴定可能调节他汀类药物诱导的LDLC降低的新基因，我们使用了来自胆固醇与药物遗传学（CAP）40mg/天辛伐他汀6周临床试验（ClinicalTrials.gov标识符：NCT00451828）的欧洲和非裔美国血统参与者的426个对照和2μM辛伐他汀处理的淋巴母细胞系（LCL）的RNA测序数据。我们将LCL基因表达的他汀类药物诱导变化与相应CAP参与者的血浆LDLC他汀类药物反应进行关联。对于鉴定出的相关性最高的基因（），我们通过比较野生型小鼠和（的小鼠同源物）中低表达（部分功能丧失）错义突变携带者之间的血浆胆固醇水平、脂蛋白谱和脂质他汀类药物反应进行后续研究。
147个人类LCL基因的他汀类药物诱导表达变化与相应CAP参与者的血浆LDLC他汀类药物反应显著相关（FDR = 5%）。相关性最强的两个基因是锌指蛋白335（又名，rho = 0.237，FDR校正p = 0.0085）和CCR4-NOT转录复合体亚基3（，rho = 0.233，FDR校正p = 0.0085）。在性别合并模型中，携带低表达错义（R1092W；又名bloto）突变的正常饮食小鼠的非HDL胆固醇水平显著低于野生型C57BL/6J小鼠（p = 0.04）。此外，携带等位基因的雄性（而非雌性）小鼠的总胆固醇和HDL胆固醇水平显著低于野生型小鼠。在另一项实验中，野生型小鼠先喂食对照饮食4周，再喂食匹配的辛伐他汀饮食4周，他汀类药物显著降低了非HDLC（雄性和雌性分别为-43±18%和-23±19%）。野生型雄性（而非雌性）小鼠的血浆LDL颗粒浓度显著降低，而携带等位基因的雄性小鼠的LDL他汀类药物反应明显减弱。
我们的和研究确定为血浆胆固醇水平和他汀类药物反应的新型调节因子，表明ZNF335活性的变化可能导致他汀类药物临床疗效的个体差异。
