Moriarty Patrick M, Varvel Stephen A, Gordts Philip L S M, McConnell Joseph P, Tsimikas Sotirios
From the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); Salveo Diagnostics, Inc, Richmond, VA (S.A.V., J.P.M.); Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center (P.L.S.M.G.), Department of Medicine, Division of Endocrinology and Metabolism (P.L.S.M.G.), and Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center (S.T.), University of California San Diego, La Jolla.
Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):580-588. doi: 10.1161/ATVBAHA.116.308704. Epub 2017 Jan 5.
Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. genotypes have different affinities for the low-density lipoprotein (LDL) receptor and LDL-related protein-1, with ε2 having the weakest binding to LDL receptor at <2% relative to ε3 and ε4. APPROACH AND RESULTS: genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4), Lp(a) mass, directly measured Lp(a)-cholesterol levels, and a variety of apoB-related lipoproteins were measured in 431 239 patients. The prevalence of traits were ε2: 7.35%, ε3: 77.56%, and ε4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in ε4/ε4 compared with ε2/ε2 genotypes and increased significantly according to genotype: ε2/ε2: 23.4 (29.2), ε2/ε3: 31.3 (38.0), ε2/ε4: 32.8 (38.5), ε3/ε3: 33.2 (39.1), ε3/ε4: 35.5 (41.6), and ε4/ε4: 38.5 (44.1) mg/dL (<0.0001). LDL-cholesterol, apoB, Lp(a)-cholesterol, LDL-cholesterol corrected for Lp(a)-cholesterol content, LDL-particle number, and small, dense LDL also had similar patterns. Patients with LDL-cholesterol ≥250 mg/dL, who are more likely to have LDL receptor mutations and reduced affinity for apoB, had higher Lp(a) levels across all apoE isoforms, but particularly in patients with ε2 alleles, compared with LDL <250 mg/dL. The lowest Lp(a) mass levels were present in patients with ε2 isoforms and lowest LDL-cholesterol.
genotypes strongly influence Lp(a) and apoB-related lipoprotein levels. This suggests that differences in affinity of apoE proteins for lipoprotein clearance receptors may affect Lp(a) catabolism, suggesting a competition between Lp(a) and apoE protein for similar receptors.
脂蛋白(a)[Lp(a)]水平由肝细胞载脂蛋白(a)合成在遗传上决定，但分解代谢途径也会影响循环水平。ε2、ε3和ε4等位基因对低密度脂蛋白(LDL)受体和LDL相关蛋白-1具有不同的亲和力，其中ε2与LDL受体的结合最弱，相对于ε3和ε4，结合率<2%。方法与结果：在431239例患者中检测了ε2/ε2、ε2/ε3、ε2/ε4、ε3/ε3、ε3/ε4和ε4/ε4基因型、Lp(a)质量、直接测量的Lp(a)胆固醇水平以及多种载脂蛋白B相关脂蛋白。ε2、ε3和ε4等位基因的患病率分别为7.35%、77.56%和15.09%。与ε2/ε2基因型相比，ε4/ε4基因型的平均(标准差)Lp(a)水平高65%，并且根据ε等位基因类型显著升高：ε2/ε2：23.4(29.2)，ε2/ε3：31.3(38.0)，ε2/ε4：32.8(38.5)，ε3/ε3：33.2(39.1)，ε3/ε4：35.5(41.6)，ε4/ε4：38.5(44.1)mg/dL(P<0.0001)。LDL胆固醇、载脂蛋白B、Lp(a)胆固醇、校正Lp(a)胆固醇含量后的LDL胆固醇、LDL颗粒数以及小而密的LDL也有类似模式。LDL胆固醇≥250mg/dL的患者更有可能存在LDL受体突变且对载脂蛋白B的亲和力降低，与LDL<250mg/dL的患者相比，所有ε等位基因亚型患者的Lp(a)水平均较高，尤其是携带ε2等位基因的患者。ε2等位基因亚型且LDL胆固醇最低的患者Lp(a)质量水平最低。
ε等位基因类型强烈影响Lp(a)和载脂蛋白B相关脂蛋白水平。这表明载脂蛋白E蛋白对脂蛋白清除受体亲和力的差异可能影响Lp(a)的分解代谢，提示Lp(a)与载脂蛋白E蛋白在类似受体上存在竞争。
