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首页> 外文期刊>The journal of clinical investigation >The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans
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The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans

机译：N342S MYLIP多态性与高总胆固醇和人类LDL受体降解增加有关

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Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain–interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.
机译：动脉粥样硬化性心血管疾病（ASCVD）影响三分之一以上的美国成年人。高胆固醇血症是可治疗ASCVD的主要危险因素，但是许多人无法通过使用他汀类药物和改变生活方式来达到LDL-胆固醇（LDL-C）的目标水平。 E3泛素连接酶肌球蛋白调节性轻链相互作用蛋白（MYLIP;也称为IDOL）是最近发现的LDL受体（LDLR）途径的调节剂。在欧洲后裔人群中的全基因组关联研究（GWAS）已确定MYLIP区域中的非编码变异与LDL-C水平相关，但没有指出潜在的功能变异。为了精确绘制实际的磁化率变异，我们研究了人口统计学上与发现种群不同的种群，以确保连锁不平衡的不同模式。我们的分析显示，在墨西哥人口中，编码N342S氨基酸取代的非同义SNP rs9370867是与高总胆固醇相关的潜在功能变体，是先前重要的GWAS信号之一。功能表征表明，编码Asn的等位基因与更有效的LDLR降解和降低的LDL摄取有关。残基342的诱变未能影响固有的MYLIP E3连接酶活性，但这对LDLR靶向至关重要。我们的发现表明，MYLIP活性的调节可影响LDL-C水平，并且MYLIP活性的药理抑制可能是治疗血脂异常和ASCVD的有用策略。

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