用于临床家族性高胆固醇血症多基因形式诊断的低密度脂蛋白胆固醇遗传风险评分的变异选择优化及在6个国家样本中的验证
Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.
作者信息
Futema Marta, Shah Sonia, Cooper Jackie A, Li KaWah, Whittall Ros A, Sharifi Mahtab, Goldberg Olivia, Drogari Euridiki, Mollaki Vasiliki, Wiegman Albert, Defesche Joep, D'Agostino Maria N, D'Angelo Antonietta, Rubba Paolo, Fortunato Giuliana, Waluś-Miarka Małgorzata, Hegele Robert A, Aderayo Bamimore Mary, Durst Ronen, Leitersdorf Eran, Mulder Monique T, Roeters van Lennep Jeanine E, Sijbrands Eric J G, Whittaker John C, Talmud Philippa J, Humphries Steve E
机构信息
Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
UCL Genetics Institute, Department of Genetics, Environment and Evolution, London, University College London, UK; Current affiliation: Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia;
出版信息
Clin Chem. 2015 Jan;61(1):231-8. doi: 10.1373/clinchem.2014.231365. Epub 2014 Nov 20.
BACKGROUND
Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples.
METHODS
We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII).
RESULTS
Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C.
CONCLUSIONS
A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.
背景
家族性高胆固醇血症（FH）是一种常染色体显性疾病，由三个基因中的一个发生突变引起。在60%的突变阴性患者中，我们最近发现，通过使用一个包含12个单核苷酸多态性（12-SNP）的评分，临床表型可能与常见的、具有较小效应的升高低密度脂蛋白胆固醇（LDL-C）的等位基因的积累有关。本研究的目的是优化单核苷酸多态性的选择，并在其他样本中重复研究结果。
方法
我们使用ROC曲线来确定LDL-C单核苷酸多态性的最佳数量。为了进行重复分析，我们对来自6个国家临床诊断为FH的患者进行基因分型，检测6个与LDL-C相关的等位基因。我们比较了未确诊突变的患者（FH/M-）、有突变的患者（FH/M+）以及来自英国人群样本（WHII）的对照组之间的加权单核苷酸多态性评分。
结果
将单核苷酸多态性的数量增加到33个并没有提高该评分区分FH/M-患者与对照组的能力，而依次去除效应较小/频率较低的单核苷酸多态性显示，6个单核苷酸多态性的加权评分与12个单核苷酸多态性的评分表现相当。基于独立的FH/M-队列中CELSR2（钙黏蛋白，EGF LAG 7跨膜G型受体2）、APOB（载脂蛋白B）、ABCG5/8 [ATP结合盒，G亚家族（白色），成员5/8]、LDLR（低密度脂蛋白受体）和APOE（载脂蛋白E）基因座的多态性对6个单核苷酸多态性加权评分进行的荟萃分析显示，与WHII人群相比，该评分始终更高（P < 2.2 × 10-16）。对评分分布在前四分之三的具有6个单核苷酸多态性评分的个体进行建模表明，其LDL-C升高的多基因解释可能性>95%。
结论
一个包含6个单核苷酸多态性的LDL-C评分能够持续区分FH/M-患者与健康个体。88%的突变阴性患者的高胆固醇血症可能具有多基因基础。
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