Civeira Fernando, Jarauta Estibaliz, Cenarro Ana, García-Otín Angel L, Tejedor Diego, Zambón Daniel, Mallen Miguel, Ros Emilio, Pocoví Miguel
Unidad de Lípidos and Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
J Am Coll Cardiol. 2008 Nov 4;52(19):1546-53. doi: 10.1016/j.jacc.2008.06.050.
The purpose of this study was to determine the frequency of mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) genes in consecutive patients with a clinical diagnosis of familial combined hyperlipidemia (FCH) in a nonresearch setting.
The lipid phenotype frequently overlaps in familial hypercholesterolemia (FH) and FCH. Detection of causative mutations in LDLR or APOB provides an unequivocal diagnosis of FH, but such genetic testing has not been systematically performed in FCH.
We used Lipochip (Progenika, Derio, Spain), a microarray that includes 203 causative mutations in LDLR and 4 APOB defects, to investigate 143 unrelated FCH patients.
Mutations of LDLR were found in 28 patients (overall prevalence, 19.6%). No APOB defects were found. Compared with patients who had a normal LDLR gene, patients with mutations had lower waist circumference (p = 0.02); significantly (p < 0.005) higher total cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apoB; nonsignificantly (p = 0.063) lower triglycerides; and a lower frequency of diabetes mellitus (22% vs. 0%, respectively; p = 0.002). Total cholesterol and apoB levels showed the best receiver-operator characteristics curves in the prediction of LDLR mutations, with areas under the curve (95% CI: of 0.750 (95% confidence interval [CI]: 0.647 to 0.853) and 0.744 (95% CI: 0.636 to 0.851), respectively. Total cholesterol of 335 mg/dl and apoB of 185 mg/dl were the best thresholds for diagnosis of LDLR mutations.
Screening for LDLR defects is advisable for patients with a clinical diagnosis of FCH showing high total cholesterol or apoB levels. Diagnostic criteria for FH should not exclude patients whose personal and familial lipid values appear to fit the clinical criteria of FCH.
本研究旨在确定在非研究环境下，连续的临床诊断为家族性混合性高脂血症（FCH）患者中低密度脂蛋白受体（LDLR）和载脂蛋白B（APOB）基因突变的频率。
家族性高胆固醇血症（FH）和FCH的脂质表型常常重叠。检测LDLR或APOB中的致病突变可明确诊断FH，但此类基因检测尚未在FCH中系统开展。
我们使用Lipochip（西班牙德利奥的Progenika公司），一种包含203个LDLR致病突变和4个APOB缺陷的微阵列，对143例无亲缘关系的FCH患者进行研究。
28例患者发现LDLR突变（总体患病率为19.6%）。未发现APOB缺陷。与LDLR基因正常的患者相比，有突变的患者腰围更低（p = 0.02）；总胆固醇、非高密度脂蛋白胆固醇、低密度脂蛋白胆固醇和载脂蛋白B显著更高（p < 0.005）；甘油三酯无显著降低（p = 0.063）；糖尿病发生率更低（分别为22%和0%；p = 0.002）。总胆固醇和载脂蛋白B水平在预测LDLR突变方面显示出最佳的受试者工作特征曲线，曲线下面积分别为0.750（95%置信区间[CI]：0.647至0.853）和0.744（95% CI：0.636至0.851）。总胆固醇335mg/dl和载脂蛋白B 185mg/dl是诊断LDLR突变的最佳阈值。
对于临床诊断为FCH且总胆固醇或载脂蛋白B水平高的患者，建议筛查LDLR缺陷。FH的诊断标准不应排除个人和家族脂质值似乎符合FCH临床标准的患者。
