Plaisier Christopher L, Horvath Steve, Huertas-Vazquez Adriana, Cruz-Bautista Ivette, Herrera Miguel F, Tusie-Luna Teresa, Aguilar-Salinas Carlos, Pajukanta Päivi
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
PLoS Genet. 2009 Sep;5(9):e1000642. doi: 10.1371/journal.pgen.1000642. Epub 2009 Sep 11.
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.
我们推测上游转录因子1（USF1）3'非翻译区的一个常见单核苷酸多态性（SNP），即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对此可能性进行了研究，该人群具有高血脂倾向。我们首先将墨西哥家族性混合性高脂血症（FCHL）病例/对照脂肪活检中的rs3737787基因型与整体表达模式相关联。为了识别由转录因子、遗传变异或环境效应等相似因素共同调控的共表达基因集，我们利用了加权基因共表达网络分析（WGCNA）。通过对墨西哥FCHL脂肪活检进行WGCNA，我们确定了两个与甘油三酯（TG）显著相关的共表达模块。其中一个模块也与FCHL、其他FCHL组分性状以及rs3737787基因型相关。这个由USF1调控的FCHL相关（URFA）模块富含参与脂质代谢过程的基因。使用系统遗传学方法，我们在URFA模块中确定了18个因果候选基因。在最近一项白种人的全基因组显著关联研究中，FCHL因果候选基因脂肪酸去饱和酶3（FADS3）与甘油三酯相关，我们在墨西哥FCHL家族中重复了这一关联。基于一个由USF1调控的FCHL相关共表达模块和SNP rs3737787，我们确定了一组与FCHL相关性状的因果候选基因。然后，我们从两个独立的数据集中提供证据，支持FADS3作为墨西哥人FCHL和甘油三酯升高的因果基因。
