De Castro-Orós Isabel, Solà Rosa, Valls Rosa María, Brea Angel, Mozas Pilar, Puzo Jose, Pocoví Miguel
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
Unidad de Lípidos, Servicio de Medicina Interna, Hospital Universitario San Pedro, Logroño, Spain.
PLoS One. 2016 Mar 25;11(3):e0150785. doi: 10.1371/journal.pone.0150785. eCollection 2016.
Armolipid Plus (AP) is a nutraceutical that contains policosanol, fermented rice with red yeast, berberine, coenzyme Q10, folic acid, and astaxanthin. It has been shown to be effective in reducing plasma LDL cholesterol (LDLc) levels. In the multicenter randomized trial NCT01562080, there was large interindividual variability in the plasma LDLc response to AP supplementation. We hypothesized that the variability in LDLc response to AP supplementation may be linked to LDLR and PCSK9 polymorphisms.
We sequenced the LDLR 3' and 5' untranslated regions (UTR) and the PCSK9 5' UTR of 102 participants with moderate hypercholesterolemia in trial NCT01562080. In this trial, 50 individuals were treated with AP supplementation and the rest with placebo.
Multiple linear regression analysis, using the response of LDLc levels to AP as the dependent variable, revealed that polymorphisms rs2149041 (c.-3383C>G) in the PCSK9 5' UTR and rs14158 (c.*52G>A) in the LDLR 3' UTR explained 14.1% and 6.4%, respectively, of the variability after adjusting for gender, age, and BMI of individuals. Combining polymorphisms rs2149041 and rs14158 explained 20.5% of this variability (p < 0.004).
Three polymorphisms in the 3' UTR region of LDLR, c.*52G>A, c.*504G>A, and c.*773A>G, and two at the 5' UTR region of PCSK9, c.-3383C>G and c.-2063A>G, were associated with response to AP. These results could explain the variability observed in the response to berberine among people with moderate hypercholesterolemia, and they may be useful in identifying patients who could potentially benefit from supplementation with AP.
Armolipid Plus（AP）是一种营养保健品，含有多廿烷醇、红曲发酵米、黄连素、辅酶Q10、叶酸和虾青素。已证明其在降低血浆低密度脂蛋白胆固醇（LDLc）水平方面有效。在多中心随机试验NCT01562080中，补充AP后血浆LDLc反应存在较大个体间差异。我们推测补充AP后LDLc反应的差异可能与LDLR和PCSK9基因多态性有关。
我们对试验NCT01562080中102名中度高胆固醇血症参与者的LDLR 3'和5'非翻译区（UTR）以及PCSK9 5'UTR进行了测序。在该试验中，50人接受AP补充治疗，其余人接受安慰剂治疗。
以LDLc水平对AP的反应作为因变量进行多元线性回归分析，结果显示，在校正个体的性别、年龄和BMI后，PCSK9 5'UTR中的rs2149041（c.-3383C>G）和LDLR 3'UTR中的rs14158（c.*52G>A）多态性分别解释了14.1%和6.4%的变异性。rs2149041和rs14158多态性组合解释了20.5%的变异性（p<0.004）。
LDLR 3'UTR区域的三个多态性，即c.*52G>A、c.*504G>A和c.*773A>G，以及PCSK9 5'UTR区域的两个多态性，即c.-3383C>G和c.-2063A>G，与对AP的反应相关。这些结果可以解释中度高胆固醇血症患者对黄连素反应中观察到的变异性，并且可能有助于识别可能从补充AP中获益的患者。
