A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis
A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis
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DOI：
10.1016/j.jacc.2005.01.051
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发表时间：
2005-05-17
影响因子：
24
通讯作者：
Marian, AJ
中科院分区：
文献类型：
--
作者：
Chen, SN;Ballantyne, CM;Marian, AJ
在脂蛋白冠状动脉粥样硬化研究（LCAS）人群中，我们试图确定PCSK 9变异体对血浆低密度脂蛋白胆固醇（LDL-C）水平、冠状动脉粥样硬化严重程度和对他汀类药物治疗反应的影响。我们假设，PCSK 9变异体可能会影响血浆LDL-C在个人与多基因hypercholesterolemia.METHODS我们测序所有12个外显子和边界，以检测新的多态性，和基因型372例受试者在LCAS和319例受试者在第二个独立的人口为6个多态性，包括新的亮氨酸重复序列，荧光标记。结果LDL-C三分位数间的总体单倍型分布差异有统计学意义（比值比[OR]：2.36，95%置信区间[CI]：1.90至4.32，p = 0.005）和冠状动脉病变的最小管腔直径（OR：1.83，95% CI：1.01至3.55，p = 0.045）。回归分析确定单倍型3为LDL-C水平的独立决定因素（校正R = 2.2%，F = 9.37，p = 0.002）。单倍型结构分析确定E670 G为决定性变异，产生剂量效应（GG > EG > EE），占血浆LDL-C变异的3.5%（F = 14.6，p < 0.001）。血浆总胆固醇、载脂蛋白13和脂蛋白（a）水平也与E670 G变异相关。E670 G基因型在一个独立的血脂正常和高血脂LCAS人群中的分布有显著差异（F = 7.2，p = 0.027）。未检测到显著的治疗-基因型相互作用。结论E670 G单倍型3是血浆LDL-C水平和冠状动脉粥样硬化严重程度的独立决定因素。(c)2005年，美国心脏病学会基金会。
OBJECTIVES We sought to determine the effects of PCSK9 variants on plasma low-density lipoprotein cholesterol (LDL-C) levels, severity of coronary atherosclerosis, and response to statin therapy in the Lipoprotein Coronary Atherosclerosis Study (LCAS) population.BACKGROUND Mutations in PCSK9 cause autosomal-dominant hypercholesterolemia. We hypothesized that PCSK9 variants could affect plasma LDL-C in individuals with polygenic hypercholesterolemia.METHODS We sequenced all 12 exons and boundaries to detect novel polymorphisms, and genotyped 372 subjects in LCAS and 319 subjects in a second independent population for six polymorphisms, including novel leucine repeats, by fluorescently tagged markers. We reconstructed haplotypes using a Bayesian algorithm.RESULTS Permutation test results showed statistically significant differences in global haplotype distribution among the tertiles of LDL-C (odds ratio [OR]: 2.36, 95% confidence interval [CI]: 1.90 to 4.32, p = 0.005) and minimum lumen diameter of coronary lesions (OR: 1.83, 95% CI: 1.01 to 3.55, p = 0.045). Regression analysis identified haplotype 3 as an independent determinant of LDL-C levels (adjusted R = 2.2%, F = 9.37, p = 0.002). Haplotype structure analysis identified E670G as the determinant variant, exerting a dose effect (GG > EG > EE) and accounting for 3.5% of plasma LDL-C variability (F = 14.6, p < 0.001). Plasma total cholesterol, apolipoprotein 13, and lipoprotein (a) levels were also associated with the E670G variant. Distributions of the E670G genotypes in an independent normolipidemic and the hyperlipidemic LCAS populations were significantly different (F = 7.2, p = 0.027). No significant treatment-by-genotype interactions were detected. The false positive report probability was between 2% and 8%.CONCLUSIONS Haplotype 3 encompassing the E670G variant is an independent determinant of plasma LDL-C levels and the severity of coronary atherosclerosis. (c) 2005 by the American College of Cardiology Foundation.