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FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression

BACKGROUND: Genome-wide association studies (GWASs) have shown that genetic variants are important determinants of free fatty acid levels. The mechanisms underlying the associations between genetic variants and free fatty acid levels are incompletely understood. Here, we aimed to identify genetic ma...

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Autores principales: He, Zhen, Zhang, Rong, Jiang, Feng, Zhang, Hong, Zhao, Aihua, Xu, Bo, Jin, Li, Wang, Tao, Jia, Wei, Jia, Weiping, Hu, Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114248/
https://www.ncbi.nlm.nih.gov/pubmed/30157936
http://dx.doi.org/10.1186/s13148-018-0545-5
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author He, Zhen
Zhang, Rong
Jiang, Feng
Zhang, Hong
Zhao, Aihua
Xu, Bo
Jin, Li
Wang, Tao
Jia, Wei
Jia, Weiping
Hu, Cheng
author_facet He, Zhen
Zhang, Rong
Jiang, Feng
Zhang, Hong
Zhao, Aihua
Xu, Bo
Jin, Li
Wang, Tao
Jia, Wei
Jia, Weiping
Hu, Cheng
author_sort He, Zhen
collection PubMed
description BACKGROUND: Genome-wide association studies (GWASs) have shown that genetic variants are important determinants of free fatty acid levels. The mechanisms underlying the associations between genetic variants and free fatty acid levels are incompletely understood. Here, we aimed to identify genetic markers that could influence diverse fatty acid levels in a Chinese population and uncover the molecular mechanisms in terms of DNA methylation and gene expression. RESULTS: We identified strong associations between single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) region and multiple polyunsaturated fatty acids. Expression quantitative trait locus (eQTL) analysis of rs174570 on FADS1 and FADS2 mRNA levels proved that minor allele of rs174570 was associated with decreased FADS1 and FADS2 expression levels (P < 0.05). Methylation quantitative trait locus (mQTL) analysis of rs174570 on DNA methylation levels in three selected regions of FADS region showed that the methylation levels at four CpG sites in FADS1, one CpG site in intragenic region, and three CpG sites in FADS2 were strongly associated with rs174570 (P < 0.05). Then, we demonstrated that methylation levels at three CpG sites in FADS1 were negatively associated with FADS1 and FADS2 expression, while two CpG sites in FADS2 were positively associated with FADS1 and FADS2 expression. Using mediation analysis, we further show that the observed effect of rs174570 on gene expression was tightly correlated with the effect predicted through association with methylation. CONCLUSIONS: Our findings suggest that genetic variants in the FADS region are major genetic modifiers that can regulate fatty acid metabolism through epigenetic gene regulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-018-0545-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-61142482018-09-04 FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression He, Zhen Zhang, Rong Jiang, Feng Zhang, Hong Zhao, Aihua Xu, Bo Jin, Li Wang, Tao Jia, Wei Jia, Weiping Hu, Cheng Clin Epigenetics Research BACKGROUND: Genome-wide association studies (GWASs) have shown that genetic variants are important determinants of free fatty acid levels. The mechanisms underlying the associations between genetic variants and free fatty acid levels are incompletely understood. Here, we aimed to identify genetic markers that could influence diverse fatty acid levels in a Chinese population and uncover the molecular mechanisms in terms of DNA methylation and gene expression. RESULTS: We identified strong associations between single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) region and multiple polyunsaturated fatty acids. Expression quantitative trait locus (eQTL) analysis of rs174570 on FADS1 and FADS2 mRNA levels proved that minor allele of rs174570 was associated with decreased FADS1 and FADS2 expression levels (P < 0.05). Methylation quantitative trait locus (mQTL) analysis of rs174570 on DNA methylation levels in three selected regions of FADS region showed that the methylation levels at four CpG sites in FADS1, one CpG site in intragenic region, and three CpG sites in FADS2 were strongly associated with rs174570 (P < 0.05). Then, we demonstrated that methylation levels at three CpG sites in FADS1 were negatively associated with FADS1 and FADS2 expression, while two CpG sites in FADS2 were positively associated with FADS1 and FADS2 expression. Using mediation analysis, we further show that the observed effect of rs174570 on gene expression was tightly correlated with the effect predicted through association with methylation. CONCLUSIONS: Our findings suggest that genetic variants in the FADS region are major genetic modifiers that can regulate fatty acid metabolism through epigenetic gene regulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-018-0545-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-29 /pmc/articles/PMC6114248/ /pubmed/30157936 http://dx.doi.org/10.1186/s13148-018-0545-5 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
He, Zhen
Zhang, Rong
Jiang, Feng
Zhang, Hong
Zhao, Aihua
Xu, Bo
Jin, Li
Wang, Tao
Jia, Wei
Jia, Weiping
Hu, Cheng
FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression
title FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression
title_full FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression
title_fullStr FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression
title_full_unstemmed FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression
title_short FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression
title_sort fads1-fads2 genetic polymorphisms are associated with fatty acid metabolism through changes in dna methylation and gene expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114248/
https://www.ncbi.nlm.nih.gov/pubmed/30157936
http://dx.doi.org/10.1186/s13148-018-0545-5
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