Shen Haiqing, Damcott Coleen M, Rampersaud Evadnie, Pollin Toni I, Horenstein Richard B, McArdle Patrick F, Peyser Patricia A, Bielak Lawrence F, Post Wendy S, Chang Yen-Pei C, Ryan Kathleen A, Miller Michael, Rumberger John A, Sheedy Patrick F, Shelton John, O'Connell Jeffrey R, Shuldiner Alan R, Mitchell Braxton D
Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Arch Intern Med. 2010 Nov 8;170(20):1850-5. doi: 10.1001/archinternmed.2010.384.
Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels.
To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals.
From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10(-68)). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10(-36)). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10(-6) in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400).
The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.
低密度脂蛋白胆固醇（LDL-C）水平升高是主要的心血管疾病危险因素。遗传因素是LDL-C水平的重要决定因素。
为了鉴定与LDL-C及亚临床冠状动脉粥样硬化相关的单核苷酸多态性，我们对841名年龄在20至80岁的无症状阿米什人进行了LDL-C全基因组关联研究，并在663名阿米什人的第二个样本中进行了重复验证。我们还对其中1018名个体进行了冠状动脉钙化（CAC）扫描。
从最初的全基因组关联研究中，载脂蛋白B-100基因（APOB）区域的一组单核苷酸多态性与LDL-C水平密切相关（P < 10(-68)）。进一步的基因分型揭示了R3500Q的存在，这是导致家族性缺陷载脂蛋白B-100的突变，在重复样本中也与LDL-C密切相关（P < 10(-36)）。R3500Q的携带者频率在先前报道的欧洲白人个体中为0.1%至0.4%，在1504名阿米什参与者的合并样本中为12%，这与奠基者效应一致。该突变在两个样本中也与CAC密切相关（两者P均< 10(-6)），分别占LDL-C水平和CAC变异的26%和7%。与非携带者相比，R3500Q携带者的LDL-C水平平均高58 mg/dL，检测到CAC的几率高4.41倍（95%置信区间，2.69 - 7.21），广泛CAC（CAC评分≥400）的几率高9.28倍（2.93 - 29.35）。
APOB中的R3500Q突变是阿米什人中LDL-C水平和CAC的主要决定因素。
