Besseling Joost, Huijgen Roeland, Martin Seth S, Hutten Barbara A, Kastelein John J P, Hovingh G Kees
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
Atherosclerosis. 2016 Mar;246:1-6. doi: 10.1016/j.atherosclerosis.2015.12.033. Epub 2015 Dec 25.
We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family.
We included heterozygous FH patients identified by genetic cascade screening in the Netherlands from 1994 to 2014. A cascade starts with identification of a genetically proven FH patient ("index patient") followed by testing in first degree relatives. If a mutation carrier is identified, their first degree relatives are tested as well, and so on. The associations between distance-to-index (expressed as family relationship) and both LDL-C levels and CVD risk, were evaluated using multivariable linear and Cox regression models.
Distance-to-index could be determined in 13,374 patients. Mean (± standard error) levels of LDL-C did not differ significantly in 1st, 2nd, 3rd, and 4th or more family members: 5.46 (1.42), 5.17 (1.42), 4.89 (1.37), and 4.58 (1.27) mmol/L, respectively (adjusted p-for-trend: 0.104). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82-1.03).
This study was the first to investigate the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a decrease of phenotype severity lends support for genetic cascade testing in FH.
我们评估了家族性高胆固醇血症（FH）表型的严重程度，即低密度脂蛋白胆固醇（LDL-C）水平升高和心血管疾病（CVD）风险，在一个家族中关系较远的患者中是否会降低。
我们纳入了1994年至2014年在荷兰通过基因级联筛查确定的杂合子FH患者。级联筛查从识别一名经基因证实的FH患者（“索引患者”）开始，随后对一级亲属进行检测。如果识别出一名突变携带者，则也对其一级亲属进行检测，依此类推。使用多变量线性和Cox回归模型评估与索引患者的距离（以家族关系表示）与LDL-C水平和CVD风险之间的关联。
在13374名患者中可以确定与索引患者的距离。第一代、第二代、第三代和第四代及以上家庭成员的LDL-C平均（±标准误）水平无显著差异：分别为5.46（1.42）、5.17（1.42）、4.89（1.37）和4.58（1.27）mmol/L（趋势校正p值：0.104）。CVD的距离增加的校正风险比为0.92（95%可信区间：0.82-1.03）。
本研究首次调查了与索引患者的距离与单基因疾病表型之间的关联。表型严重程度没有降低支持了FH的基因级联检测。
