Versmissen Jorie, Oosterveer Daniëlla M, Yazdanpanah Mojgan, Dehghan Abbas, Hólm Hilma, Erdman Jeanette, Aulchenko Yurii S, Thorleifsson Gudmar, Schunkert Heribert, Huijgen Roeland, Vongpromek Ranitha, Uitterlinden André G, Defesche Joep C, van Duijn Cornelia M, Mulder Monique, Dadd Tony, Karlsson Hróbjartur D, Ordovas Jose, Kindt Iris, Jarman Amelia, Hofman Albert, van Vark-van der Zee Leonie, Blommesteijn-Touw Adriana C, Kwekkeboom Jaap, Liem Anho H, van der Ouderaa Frans J, Calandra Sebastiano, Bertolini Stefano, Averna Maurizio, Langslet Gisle, Ose Leiv, Ros Emilio, Almagro Fátima, de Leeuw Peter W, Civeira Fernando, Masana Luis, Pintó Xavier, Simoons Maarten L, Schinkel Arend F L, Green Martin R, Zwinderman Aeilko H, Johnson Keith J, Schaefer Arne, Neil Andrew, Witteman Jacqueline C M, Humphries Steve E, Kastelein John J P, Sijbrands Eric J G
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Eur J Hum Genet. 2015 Mar;23(3):381-7. doi: 10.1038/ejhg.2014.101. Epub 2014 Jun 11.
Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.
低密度脂蛋白受体（LDLR）基因突变会导致家族性高胆固醇血症（FH），这是一种以年轻时患冠心病（CHD）为特征的疾病。我们旨在应用一种极端抽样方法来提高统计效力，以识别FH患者中CHD的新遗传风险变异。我们从荷兰的17000名FH患者中选择了CHD风险具有极端差异的病例和对照，这些患者的功能性LDLR突变已明确确定。使用Illumina HumanHap550K芯片对249例非常年轻的患有CHD的FH病例和217例无CHD的老年FH对照（男性65岁以上，女性70岁以上）进行了全基因组关联（GWA）研究。在下一阶段，将两个独立的FH患者样本（一个来自荷兰，一个来自意大利、挪威、西班牙和英国）用作重复样本。在最初的GWA分析中，我们鉴定出29个与早发性CHD有提示性关联的独立单核苷酸多态性（SNP）（P<1×10⁻⁴）。我们在重复样本中检查了这些SNP与CHD风险的关联。经过Bonferroni校正后，在合并发现样本和重复样本后，没有一个SNP能够重复或达到全基因组显著性。因此，我们得出结论，FH中CHD风险的遗传学很复杂，即使应用“极端遗传学”方法，我们也没有识别出新的遗传风险变异。很可能，这种方法在利用效应大小方面不如预期有效，因此可能不会在统计效力上带来显著提高。
