A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.
A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.
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系统遗传学方法暗示了USF1，FADS3和其他因果候选基因的家族性高脂血症。
DOI：
10.1371/journal.pgen.1000642
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Pajukanta P
中科院分区：
文献类型：
--
作者：
Plaisier CL;Horvath S;Huertas-Vazquez A;Cruz-Bautista I;Herrera MF;Tusie-Luna T;Aguilar-Salinas C;Pajukanta P
我们假设上游转录因子1（USF 1）3'非翻译区中的常见SNP rs3737787可能通过影响基因表达水平来影响脂质性状，并且我们利用墨西哥人群调查了这种可能性，该人群具有高血脂症倾向。我们首先将墨西哥家族性联合高脂血症（FCHL）病例/对照脂肪活检中的rs3737787基因型与全球表达模式相关联。为了识别由类似因子（如转录因子、遗传变异或环境影响）共同调控的共表达基因集，我们利用加权基因共表达网络分析（WGCNA）。通过墨西哥FCHL脂肪活检中的WGCNA，我们确定了两个显著的甘油三酯（TG）相关的共表达模块。其中一个模块还与FCHL、其他FCHL组分性状和rs3737787基因型相关。这种USF 1调控的FCHL相关（URFA）模块富含参与脂质代谢过程的基因。使用系统遗传学程序，我们确定了18个因果候选基因的URFA模块。在最近的一项高加索人全基因组显着关联研究中，FCHL因果候选基因脂肪酸去饱和酶3（FADS 3）与TG相关，我们在墨西哥FCHL家族中复制了这种关联。基于USF 1调控的FCHL相关共表达模块和SNP rs3737787，我们确定了一组FCHL相关性状的因果候选基因。然后，我们提供了来自两个独立数据集的证据，支持FADS 3作为墨西哥人FCHL和TG升高的致病基因。通过整合遗传多态性与全基因组基因表达水平，我们能够归因于USF 1基因的遗传多态性的功能。USF 1基因以前与常见的血脂异常FCHL相关。FCHL的特征是总胆固醇、甘油三酯或两者水平升高。我们证明，这种基因多态性USF 1有助于FCHL疾病的风险，通过调节一组基因的表达功能相关的脂质代谢，这种调制是由USF 1介导的。其中一个基因的表达是由USF 1调节的FADS 3，这也涉及到最近的全基因组关联研究的脂质性状。我们证明了FADS 3区域的遗传多态性与高加索人GWAS研究中的甘油三酯相关，也与墨西哥FCHL家族中的甘油三酯相关。我们的分析为FCHL疾病风险的基因表达谱提供了新的见解，并将FADS 3鉴定为墨西哥人FCHL的新基因。
We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans. By integrating a genetic polymorphism with genome-wide gene expression levels, we were able to attribute function to a genetic polymorphism in the USF1 gene. The USF1 gene has previously been associated with a common dyslipidemia, FCHL. FCHL is characterized by elevated levels of total cholesterol, triglycerides, or both. We demonstrate that this genetic polymorphism in USF1 contributes to FCHL disease risk by modulating the expression of a group of genes functionally related to lipid metabolism, and that this modulation is mediated by USF1. One of the genes whose expression is modulated by USF1 is FADS3, which was also implicated in a recent genome-wide association study for lipid traits. We demonstrated that a genetic polymorphism from the FADS3 region, which was associated with triglycerides in a GWAS study of Caucasians, was also associated with triglycerides in Mexican FCHL families. Our analysis provides novel insight into the gene expression profile contributing to FCHL disease risk, and identifies FADS3 as a new gene for FCHL in Mexicans.
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5.2
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