A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia

Abstract

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.

Author Summary

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.