From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine (T.K., A,G., H.W., M.F.), Wellcome Trust Centre for Human Genetics (T.K., A.G., H.W., M.F.), and Clinical Trial Service Unit and Epidemiological Studies Unit (J.C.H., R.C.), University of Oxford, Oxford, United Kingdom; and Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany (U.S.).
Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2095-9. doi: 10.1161/ATVBAHA.114.303462. Epub 2014 Jun 12.
Increased levels of lipoprotein(a) are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of lipoprotein(a) levels are mainly because of genetic variation in the apolipoprotein(a) gene (LPA). We have tested the association of a relatively common null allele of LPA with lipoprotein(a) levels and CAD risk in a large case-control cohort. We have also examined how null allele genotyping complements apolipoprotein(a) isoform typing to refine the relationship between LPA isoform size and circulating lipoprotein(a) levels.
The LPA null allele (rs41272114) was genotyped in the PROCARDIS (Precocious Coronary Artery Disease) case-control cohort (4073 CAD cases and 4225 controls). Lipoprotein(a) levels were measured in 909 CAD cases and 922 controls; apolipoprotein(a) isoform size was estimated using sodium dodecyl sulfate-agarose gel electrophoresis and a high-throughput quantitative polymerase chain reaction-based method. Null carriers are common (null allele frequency, 3%) and have significantly lower circulating lipoprotein(a) levels (P=2.1×10(-10)) and reduced CAD risk (odds ratio, 0.79 [0.66-0.97]; P=0.023) compared with noncarriers. An additive allelic model of apolipoprotein(a) isoform size, refined by null allele genotype and quantitative polymerase chain reaction values, showed a sigmoid relationship with lipoprotein(a) levels, with baseline levels for longer isoform alleles and progressively higher levels of lipoprotein(a) for shorter isoform alleles.
The LPA null allele (rs41272114) is associated with decreased circulating lipoprotein(a) levels and decreased CAD risk. Incorporating rs41272114 refined apolipoprotein(a) isoform size typing obtained by immunoblotting and quantitative polymerase chain reaction. A joint genomic and isoform analysis revealed details of the relationship between apolipoprotein(a) isoform size and circulating lipoprotein(a) level consistent with a threshold effect on lipoprotein secretion.
脂蛋白(a)水平升高是冠心病（CAD）的一个高度遗传性危险因素。脂蛋白(a)水平的遗传决定因素主要是由于载脂蛋白(a)基因（LPA）的遗传变异。我们已经在一个大型病例对照队列中测试了 LPA 相对常见的无效等位基因与脂蛋白(a)水平和 CAD 风险的关联。我们还研究了无效等位基因基因分型如何补充载脂蛋白(a)同工型分型，以细化 LPA 同工型大小与循环脂蛋白(a)水平之间的关系。
PROCARDIS（早发性冠状动脉疾病）病例对照队列（4073 例 CAD 病例和 4225 例对照）中对 LPA 无效等位基因（rs41272114）进行了基因分型。909 例 CAD 病例和 922 例对照中测量了脂蛋白(a)水平；使用十二烷基硫酸钠-琼脂糖凝胶电泳和高通量定量聚合酶链反应（PCR）法估计载脂蛋白(a)同工型大小。无效载体很常见（无效等位基因频率为 3%），与非载体相比，其循环脂蛋白(a)水平显著降低（P=2.1×10(-10)），CAD 风险降低（比值比，0.79 [0.66-0.97]；P=0.023）。载脂蛋白(a)同工型大小的加性等位基因模型，通过无效等位基因基因型和定量 PCR 值进行细化，与脂蛋白(a)水平呈 S 型关系，长同工型等位基因的基线水平和短同工型等位基因的脂蛋白(a)水平逐渐升高。
LPA 无效等位基因（rs41272114）与循环脂蛋白(a)水平降低和 CAD 风险降低相关。通过免疫印迹和定量 PCR 获得的 rs41272114 细化载脂蛋白(a)同工型大小分型，纳入其中。基因组和同工型联合分析揭示了载脂蛋白(a)同工型大小与循环脂蛋白(a)水平之间关系的细节，与脂蛋白分泌的阈值效应一致。
