A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.
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 dysl...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-09-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2730565?pdf=render |
| _version_ | 1818416165046714368 |
|---|---|
| author | Christopher L Plaisier Steve Horvath Adriana Huertas-Vazquez Ivette Cruz-Bautista Miguel F Herrera Teresa Tusie-Luna Carlos Aguilar-Salinas Päivi Pajukanta |
| author_facet | Christopher L Plaisier Steve Horvath Adriana Huertas-Vazquez Ivette Cruz-Bautista Miguel F Herrera Teresa Tusie-Luna Carlos Aguilar-Salinas Päivi Pajukanta |
| author_sort | Christopher L Plaisier |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T11:46:33Z |
| format | Article |
| id | doaj.art-d8a33149d333492fa2f6be7815df4399 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-14T11:46:33Z |
| publishDate | 2009-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-d8a33149d333492fa2f6be7815df43992022-12-21T23:02:33ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-09-0159e100064210.1371/journal.pgen.1000642A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.Christopher L PlaisierSteve HorvathAdriana Huertas-VazquezIvette Cruz-BautistaMiguel F HerreraTeresa Tusie-LunaCarlos Aguilar-SalinasPäivi PajukantaWe 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.http://europepmc.org/articles/PMC2730565?pdf=render |
| spellingShingle | Christopher L Plaisier Steve Horvath Adriana Huertas-Vazquez Ivette Cruz-Bautista Miguel F Herrera Teresa Tusie-Luna Carlos Aguilar-Salinas Päivi Pajukanta A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. PLoS Genetics |
| title | A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. |
| title_full | A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. |
| title_fullStr | A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. |
| title_full_unstemmed | A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. |
| title_short | A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. |
| title_sort | systems genetics approach implicates usf1 fads3 and other causal candidate genes for familial combined hyperlipidemia |
| url | http://europepmc.org/articles/PMC2730565?pdf=render |
| work_keys_str_mv | AT christopherlplaisier asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT stevehorvath asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT adrianahuertasvazquez asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT ivettecruzbautista asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT miguelfherrera asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT teresatusieluna asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT carlosaguilarsalinas asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT paivipajukanta asystemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT christopherlplaisier systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT stevehorvath systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT adrianahuertasvazquez systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT ivettecruzbautista systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT miguelfherrera systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT teresatusieluna systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT carlosaguilarsalinas systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia AT paivipajukanta systemsgeneticsapproachimplicatesusf1fads3andothercausalcandidategenesforfamilialcombinedhyperlipidemia |