Sjouke Barbara, Yahya Reyhana, Tanck Michael W T, Defesche Joep C, de Graaf Jacqueline, Wiegman Albert, Kastelein John J P, Mulder Monique T, Hovingh G Kees, Roeters van Lennep Jeanine E
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Department of Internal Medicine, Erasmus Medical Centre, Erasmus University of Rotterdam, Rotterdam, The Netherlands.
J Clin Lipidol. 2017 Mar-Apr;11(2):507-514. doi: 10.1016/j.jacl.2017.02.010. Epub 2017 Feb 27.
Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and in some studies also high lipoprotein(a) (Lp(a)) levels were observed. The question remains whether this effect on Lp(a) levels is gene-dose-dependent in individuals with either 0, 1, or 2 LDLR or APOB mutations.
We set out to study whether Lp(a) levels differ among bi-allelic ADH mutation carriers, and their relatives, in the Netherlands.
Bi-allelic ADH mutation carriers were identified in the database of the national referral laboratory for DNA diagnostics of inherited dyslipidemias. Family members were invited by the index cases to participate. Clinical parameters and Lp(a) levels were measured in bi-allelic ADH mutation carriers and their heterozygous and unaffected relatives.
We included a total of 119 individuals; 34 bi-allelic ADH mutation carriers (20 homozygous/compound heterozygous LDLR mutation carriers (HoFH), 2 homozygous APOB mutation carriers (HoFDB), and 12 double heterozygotes for an LDLR and APOB mutation), 63 mono-allelic ADH mutation carriers (50 heterozygous LDLR [HeFH], 13 heterozygous APOB [HeFDB] mutation carriers), and 22 unaffected family members. Median Lp(a) levels in unaffected relatives, HeFH, and HoFH patients were 19.9 (11.1-41.5), 24.4 (5.9-70.6), and 47.3 (14.9-111.7) mg/dL, respectively (P = .150 for gene-dose dependency). Median Lp(a) levels in HeFDB and HoFDB patients were 50.3 (18.7-120.9) and 205.5 (no interquartile range calculated), respectively (P = .012 for gene-dose-dependency). Double heterozygous carriers of LDLR and APOB mutations had median Lp(a) levels of 27.0 (23.5-45.0), which did not significantly differ from HoFH and HoFDB patients (P = .730 and .340, respectively).
A (trend toward) increased plasma Lp(a) levels in homozygous ADH patients compared with both heterozygous ADH and unaffected relatives was observed. Whether increased Lp(a) levels in homozygous ADH patients add to the increased cardiovascular disease risk and whether this risk can be reduced by therapies that lower both low-density lipoprotein cholesterol and Lp(a) levels remains to be elucidated.
常染色体显性遗传性高胆固醇血症（ADH）患者，由低密度脂蛋白受体（LDLR）、载脂蛋白B（APOB）或前蛋白转化酶枯草杆菌蛋白酶9型（PCSK9）的突变引起，其特征为低密度脂蛋白胆固醇水平升高，并且在一些研究中还观察到脂蛋白（a）[Lp（a）]水平升高。对于携带0、1或2个LDLR或APOB突变的个体，这种对Lp（a）水平的影响是否存在基因剂量依赖性，仍是一个问题。
我们着手研究荷兰双等位基因ADH突变携带者及其亲属的Lp（a）水平是否存在差异。
在国家遗传性血脂异常DNA诊断转诊实验室的数据库中识别双等位基因ADH突变携带者。索引病例邀请家庭成员参与。对双等位基因ADH突变携带者及其杂合子和未受影响的亲属测量临床参数和Lp（a）水平。
我们共纳入了119名个体；34名双等位基因ADH突变携带者（20名纯合子/复合杂合子LDLR突变携带者[HoFH]，2名纯合子APOB突变携带者[HoFDB]，以及12名LDLR和APOB突变的双杂合子），63名单等位基因ADH突变携带者（50名杂合子LDLR[HeFH]，13名杂合子APOB[HeFDB]突变携带者），以及22名未受影响的家庭成员。未受影响的亲属、HeFH和HoFH患者的Lp（a）水平中位数分别为19.9（11.1 - 41 .5）、24.4（5.9 - 70.6）和47.3（14.9 - 111.7）mg/dL（基因剂量依赖性P = 0.150）。HeFDB和HoFDB患者的Lp（a）水平中位数分别为50.3（18.7 - 120.9）和205.5（未计算四分位数间距）（基因剂量依赖性P = 0.012）。LDLR和APOB突变的双杂合子携带者的Lp（a）水平中位数为27.0（23.5 - 45.0），与HoFH和HoFDB患者无显著差异（分别为P = 0.730和0.340）。
观察到与杂合子ADH患者和未受影响的亲属相比纯合子ADH患者血浆Lp（a）水平有升高（趋势）。纯合子ADH患者Lp（a）水平升高是否会增加心血管疾病风险，以及这种风险是否可以通过降低低密度脂蛋白胆固醇和Lp（a）水平的治疗来降低，仍有待阐明。
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