Lingenhel A, Kraft H G, Kotze M, Peeters A V, Kronenberg F, Kruse R, Utermann G
Institut für Medizinische Biologie und Humangenetik, Universität Innsbruck, Austria.
Eur J Hum Genet. 1998 Jan;6(1):50-60. doi: 10.1038/sj.ejhg.5200152.
Lipoprotein(a) (Lp(a)) is a complex in human plasma assembled from low-density lipoprotein (LDL) and apolipoprotein(a) (apo(a)). High plasma concentrations of Lp(a) are a risk factor for coronary heart disease (CHD) in particular in patients with concomitant elevation of LDL. We have analysed for elevated Lp(a) levels in patients with familial hypercholesterolaemia (FH), a condition caused by mutations in the LDL receptor (LDLR) gene and characterised by high LDL, xanthomatosis and premature CHD. To avoid possible confusion by the apo(a) gene which is the major quantitative trait locus controlling Lp(a) in the population at large, we used a sib pair approach based on genotype information for both the LDLR and the apo(a) gene. We analysed 367 family members of 30 South African and 30 French Canadian index patients with FH for LDLR mutations and for apo(a) genotype. Three lines of evidence showed a significant effect of FH on Lp(a) levels: (1) Lp(a) values were significantly higher in FH individuals compared to non-FH relatives (p < 0.001), although the distribution of apo(a) alleles was not different in the two groups; (2) comparison of Lp(a) concentrations in 28 sib pairs, identical by descent (i.b.d.) at the apo(a) locus but non-identical for LDLR status, extracted from this large sample demonstrated significantly elevated Lp(a) concentrations in sibs with FH (p < 0.001); (3) single i.b.d. apo(a) alleles were associated with significantly higher Lp(a) concentrations (p < 0.0001) in FH than non-FH family members. Variability in associated Lp(a) levels also depended on FH status and was highest when i.b.d. alleles were present in FH subjects and lowest when present in non-FH individuals. The study demonstrates that sib pair analysis makes it possible to detect the effect of a minor gene in the presence of the effect of a major gene. Given the interactive effect of elevated LDL and high Lp(a) on CHD risk our data suggest that elevated Lp(a) may add to the CHD risk in FH subjects.
脂蛋白(a)[Lp(a)]是人体血浆中由低密度脂蛋白(LDL)和载脂蛋白(a)[apo(a)]组装而成的一种复合物。血浆Lp(a)浓度升高是冠心病(CHD)的一个危险因素，尤其是在LDL同时升高的患者中。我们分析了家族性高胆固醇血症(FH)患者的Lp(a)水平，FH是一种由低密度脂蛋白受体(LDLR)基因突变引起的疾病，其特征是LDL水平高、黄瘤病和早发性冠心病。为避免apo(a)基因可能造成的混淆，该基因是控制人群中Lp(a)的主要数量性状位点，我们基于LDLR和apo(a)基因的基因型信息采用了同胞对方法。我们分析了30名南非和30名法裔加拿大FH指数患者的367名家庭成员的LDLR突变和apo(a)基因型。三条证据表明FH对Lp(a)水平有显著影响：(1)与非FH亲属相比，FH个体的Lp(a)值显著更高(p<0.001)，尽管两组apo(a)等位基因的分布没有差异；(2)从这个大样本中提取的28对apo(a)位点同源相同(i.b.d.)但LDLR状态不同的同胞对中，Lp(a)浓度的比较显示，FH同胞的Lp(a)浓度显著升高(p<0.001)；(3)单个i.b.d. apo(a)等位基因与FH家庭成员的Lp(a)浓度显著升高相关(p<0.0001)，高于非FH家庭成员。相关Lp(a)水平的变异性也取决于FH状态，当i.b.d.等位基因存在于FH受试者中时最高，而存在于非FH个体中时最低。该研究表明，同胞对分析使得在存在主要基因效应的情况下检测次要基因的效应成为可能。鉴于升高的LDL和高Lp(a)对CHD风险的交互作用，我们的数据表明，升高的Lp(a)可能会增加FH受试者的CHD风险。
