A genome-wide study of lipid response to fenofibrate in Caucasians: a combined analysis of the GOLDN and ACCORD studies
A genome-wide study of lipid response to fenofibrate in Caucasians: a combined analysis of the GOLDN and ACCORD studies
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DOI：
10.1097/fpc.0000000000000219
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发表时间：
2016-07-01
影响因子：
2.6
通讯作者：
Arnett, Donna K.
中科院分区：
文献类型：
--
作者：
Irvin, Marguerite R.;Rotroff, Daniel M.;Arnett, Donna K.
贝特类药物通常用于治疗高甘油三酯血症，但它们也能降低低密度脂蛋白胆固醇，增加高密度脂蛋白胆固醇。脂质反应的巨大个体间差异表明，一些患者可能比其他患者受益更多，基因研究可以帮助识别这些患者。方法采用两项具有良好特征的临床试验：降脂药物和饮食网络（GOLDN）研究和糖尿病心血管风险控制（ACCORD）研究的数据，进行了非诺贝特对脂质反应的首次全基因组关联研究。两项研究的全基因组关联研究数据被输入到1000个基因组CEU参考面板（第一阶段）。脂质反应建模为治疗后脂质水平与治疗前水平的对数比。采用线性混合模型（GOLDN，来自173个家族的N=813）和线性回归模型（ACCORD， N=781）对预处理脂质水平、人口统计学变量、临床协变量和祖先进行校正，评估遗传标记与脂质反应的关系。在白种人中，使用反方差加权固定效应荟萃分析合并结果。meta分析的主要结果在HyperTG研究（N=267西班牙裔）和ACCORD研究（N=83西班牙裔，138非洲裔美国人）的其他种族群体中进行了检验。结果19号染色体上含有前b细胞白血病同源盒4 （PBX4）基因的脂质位点对LDL胆固醇对非诺贝特的反应很重要（最小P=1.5x10(-8)）。主要结果在西班牙裔美国人的ACCORD (P
Background Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients.Methods We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans).Results A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5x10(-8)). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P