RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.
RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.
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DOI：
10.1161/circgenetics.115.001274
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Medina MW
中科院分区：
文献类型：
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作者：
Mitchel K;Theusch E;Cubitt C;Dosé AC;Stevens K;Naidoo D;Medina MW
通过全基因组关联研究（GWAS）已经确定了许多导致心血管疾病风险的遗传因素;然而，确定这些关联的分子机制并不简单。瑞舒伐他汀使用者的JUPITER试验确定了rs6924995（MYLIP（又名IDOL，LDLR的诱导性降解物）下游约10 kb的SNP）与LDL胆固醇他汀类药物反应的亚基因组范围关联。有趣的是，虽然这个信号最初归因于MYLIP，但rs6924995位于RP 1 -13D10.2（一种未表征的长非编码RNA）内。使用来自胆固醇和药物遗传学辛伐他汀临床试验参与者的辛伐他汀和假孵育的淋巴母细胞样细胞系，我们发现他汀类药物诱导的RP 1 - 13 D10. 2水平变化在来自高加索人和非洲裔美国人LDLC应答分布尾部的细胞系之间存在差异，而在MYLIP中未观察到差异。RP 1 -13D10.2在Huh 7和HepG 2中的过表达增加了LDLR转录水平，增加了LDL摄取，并降低了APOB的培养基水平。此外，我们发现rs6924995“A”与“G”等位基因转染的肝癌细胞之间RP 1 -13D10.2过表达对LDLR转录水平的影响存在轻微差异的趋势，并提示CAP LCL中rs6924995和RP 1 -10D13.2表达水平之间存在相关性。最后，RP 1 -13D10.2的表达水平似乎是固醇调节的，这与其作为新型脂质调节剂的潜在作用一致。RP 1 -13D10.2是一种长的非编码RNA，可调节LDLR，并可能有助于LDLC对他汀类药物治疗的反应。这些发现突出了非编码RNA作为药物反应个体间差异的决定因素的潜在作用。
Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies (GWAS); however, identifying the molecular mechanism underlying these associations is not straightforward. The JUPITER trial of rosuvastatin users identified a sub-genome wide association of rs6924995, a SNP ~10kb downstream of MYLIP (aka IDOL, inducible degrader of LDLR), with LDL cholesterol statin response. Interestingly, though this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA. Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics simvastatin clinical trial, we found that statin induced change in RP1-13D10.2 levels differed between cell lines from the tails of the Caucasian and African American LDLC response distributions, while no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of APOB. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 “A” vs. “G” allele, and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP LCLs. Lastly, RP1-13D10.2 expression levels appear to be sterol regulated, consistent with its potential role as a novel lipid regulator. RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to LDLC response to statin treatment. These findings highlight the potential role of non-coding RNAs as determinants of inter-individual variation in drug response.