PDF(Pubmed)
Abstract：
UNASSIGNED: Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder characterized by increased circulating low-density lipoprotein cholesterol and accelerated atherosclerosis. Even among this high-risk group, prior studies note considerable variability in risk of coronary artery disease (CAD).
UNASSIGNED: The purpose of this study was to evaluate the cumulative impact of many common DNA variants-as quantified by a polygenic score-on incident CAD among individuals carrying a HeFH variant.
UNASSIGNED: We analyzed data from a prospective cohort study of 1,315 individuals who carried a HeFH variant and 1,315 matched family noncarriers derived from a nationwide screening program in the Netherlands, with subsequent replication in 151,009 participants of the UK Biobank.
UNASSIGNED: Despite identification and lipid management within the Dutch screening program, 84 (6.4%) of HeFH variant carriers developed CAD as compared to 45 (3.4%) of matched family members (median follow-up 10.2 years, HR 1.88, 95% CI: 1.31-2.70). Among HeFH variant carriers, a polygenic score was associated with CAD with an effect size similar to low-density lipoprotein cholesterol - HR of 1.35 (95% CI: 1.07-1.70) and 1.41 (95% CI: 1.17-1.70) per standard deviation increase, respectively. When compared to noncarriers, CAD risk increased from 1.24-fold (95% CI: 0.64-2.34) to 3.37-fold (95% CI: 2.11-5.36) across quintiles of the polygenic score. A similar risk gradient, 1.36-fold (95% CI: 0.65-2.85) to 2.88-fold (95% CI: 1.59-5.20), was observed in 429 carriers in the UK Biobank.
UNASSIGNED: In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.
UNASSIGNED: The purpose of this study was to evaluate the cumulative impact of many common DNA variants-as quantified by a polygenic score-on incident CAD among individuals carrying a HeFH variant.
UNASSIGNED: We analyzed data from a prospective cohort study of 1,315 individuals who carried a HeFH variant and 1,315 matched family noncarriers derived from a nationwide screening program in the Netherlands, with subsequent replication in 151,009 participants of the UK Biobank.
UNASSIGNED: Despite identification and lipid management within the Dutch screening program, 84 (6.4%) of HeFH variant carriers developed CAD as compared to 45 (3.4%) of matched family members (median follow-up 10.2 years, HR 1.88, 95% CI: 1.31-2.70). Among HeFH variant carriers, a polygenic score was associated with CAD with an effect size similar to low-density lipoprotein cholesterol - HR of 1.35 (95% CI: 1.07-1.70) and 1.41 (95% CI: 1.17-1.70) per standard deviation increase, respectively. When compared to noncarriers, CAD risk increased from 1.24-fold (95% CI: 0.64-2.34) to 3.37-fold (95% CI: 2.11-5.36) across quintiles of the polygenic score. A similar risk gradient, 1.36-fold (95% CI: 0.65-2.85) to 2.88-fold (95% CI: 1.59-5.20), was observed in 429 carriers in the UK Biobank.
UNASSIGNED: In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.
摘要：
杂合性家族性高胆固醇血症（HeFH）是一种单基因疾病，其特征是循环低密度脂蛋白胆固醇增加和动脉粥样硬化加速。即使在这个高危人群中，先前的研究指出，冠状动脉疾病（CAD）的风险存在相当大的差异。
■这项研究的目的是评估许多常见DNA变体的累积影响-通过多基因评分量化-在携带HeFH变体的个体中发生CAD。
我们分析了一项前瞻性队列研究的数据，该研究包括1,315名携带HeFH变体的个体和1,315名匹配的家族非携带者，这些非携带者来自荷兰的一项全国性筛查计划。随后在英国生物库的151,009名参与者中复制。
■尽管在荷兰筛查计划中进行了鉴定和脂质管理，84（6.4％）的HeFH变异体携带者发展为CAD，而45（3.4％）的匹配家庭成员（中位随访10.2年，HR1.88，95%CI：1.31-2.70）。在HeFH变体携带者中，多基因评分与CAD的效应大小相似，低密度脂蛋白胆固醇-HR为1.35（95％CI：1.07-1.70）和1.41（95％CI：1.17-1.70），分别。与非携带者相比，在多基因评分的五分之一中，CAD风险从1.24倍（95％CI：0.64-2.34）增加到3.37倍（95％CI：2.11-5.36）。类似的风险梯度，1.36倍（95%CI：0.65-2.85）至2.88倍（95%CI：1.59-5.20），在英国生物库的429个携带者中观察到。
■在2项队列研究中，涉及1,744名遗传证实为HeFH的个体-迄今为止最大的研究-CAD的风险因多基因背景而异，在某些情况下，接近非携带者观察到的风险。
■这项研究的目的是评估许多常见DNA变体的累积影响-通过多基因评分量化-在携带HeFH变体的个体中发生CAD。
我们分析了一项前瞻性队列研究的数据，该研究包括1,315名携带HeFH变体的个体和1,315名匹配的家族非携带者，这些非携带者来自荷兰的一项全国性筛查计划。随后在英国生物库的151,009名参与者中复制。
■尽管在荷兰筛查计划中进行了鉴定和脂质管理，84（6.4％）的HeFH变异体携带者发展为CAD，而45（3.4％）的匹配家庭成员（中位随访10.2年，HR1.88，95%CI：1.31-2.70）。在HeFH变体携带者中，多基因评分与CAD的效应大小相似，低密度脂蛋白胆固醇-HR为1.35（95％CI：1.07-1.70）和1.41（95％CI：1.17-1.70），分别。与非携带者相比，在多基因评分的五分之一中，CAD风险从1.24倍（95％CI：0.64-2.34）增加到3.37倍（95％CI：2.11-5.36）。类似的风险梯度，1.36倍（95%CI：0.65-2.85）至2.88倍（95%CI：1.59-5.20），在英国生物库的429个携带者中观察到。
■在2项队列研究中，涉及1,744名遗传证实为HeFH的个体-迄今为止最大的研究-CAD的风险因多基因背景而异，在某些情况下，接近非携带者观察到的风险。
