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Identification of a functional FADS1 3'UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels.
J Clin Lipidol. 2018 Sep - Oct; 12(5):1280-1289.JC

Abstract

BACKGROUND

Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes.

OBJECTIVE

Here, we sought to identify the functional variant(s) within the FADS gene cluster.

METHODS

To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays.

RESULTS

The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor.

CONCLUSION

This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes.

Authors+Show Affiliations

Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU, Lille, France.Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Laboratoire d'Épidémiologie et de Santé Publique, EA 3430, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.Laboratoire d'Épidémiologie et de Santé Publique, EA 3430, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.CarMen, INSERM 1060, University Lyon 1, INRA U1235, CRNH Rhônes-Alpes, Lyon, France.UMR INSERM 1027, Département d'Épidémiologie et de Santé Publique, Université Paul Sabatier, Toulouse Purpan, Toulouse, France.UMR INSERM 1027, Département d'Épidémiologie et de Santé Publique, Université Paul Sabatier, Toulouse Purpan, Toulouse, France.Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Clermont-Ferrand, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France. Electronic address: julie.dumont@pasteur-lille.fr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30170993

Citation

Hermant, Xavier, et al. "Identification of a Functional FADS1 3'UTR Variant Associated With Erythrocyte N-6 Polyunsaturated Fatty Acids Levels." Journal of Clinical Lipidology, vol. 12, no. 5, 2018, pp. 1280-1289.
Hermant X, Delay C, Flaig A, et al. Identification of a functional FADS1 3'UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels. J Clin Lipidol. 2018;12(5):1280-1289.
Hermant, X., Delay, C., Flaig, A., Luque-Bedregal, J., Briand, G., Bout, M. A., Cottel, D., Wagner, A., Arveiler, D., Simon, C., Ferrières, J., Ruidavets, J. B., Laillet, B., Amouyel, P., Dallongeville, J., Meirhaeghe, A., & Dumont, J. (2018). Identification of a functional FADS1 3'UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels. Journal of Clinical Lipidology, 12(5), 1280-1289. https://doi.org/10.1016/j.jacl.2018.07.012
Hermant X, et al. Identification of a Functional FADS1 3'UTR Variant Associated With Erythrocyte N-6 Polyunsaturated Fatty Acids Levels. J Clin Lipidol. 2018 Sep - Oct;12(5):1280-1289. PubMed PMID: 30170993.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of a functional FADS1 3'UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels. AU - Hermant,Xavier, AU - Delay,Charlotte, AU - Flaig,Amandine, AU - Luque-Bedregal,Jimena, AU - Briand,Gilbert, AU - Bout,Marie-Adélaïde, AU - Cottel,Dominique, AU - Wagner,Aline, AU - Arveiler,Dominique, AU - Simon,Chantal, AU - Ferrières,Jean, AU - Ruidavets,Jean-Bernard, AU - Laillet,Brigitte, AU - Amouyel,Philippe, AU - Dallongeville,Jean, AU - Meirhaeghe,Aline, AU - Dumont,Julie, Y1 - 2018/07/31/ PY - 2018/03/13/received PY - 2018/06/14/revised PY - 2018/07/13/accepted PY - 2018/9/2/pubmed PY - 2019/10/8/medline PY - 2018/9/2/entrez KW - Desaturase KW - FADS1 KW - Functional variant KW - Gene polymorphism KW - Genetic epidemiology KW - Polyunsaturated fatty acids KW - miRNA SP - 1280 EP - 1289 JF - Journal of clinical lipidology JO - J Clin Lipidol VL - 12 IS - 5 N2 - BACKGROUND: Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. OBJECTIVE: Here, we sought to identify the functional variant(s) within the FADS gene cluster. METHODS: To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. RESULTS: The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. CONCLUSION: This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes. SN - 1933-2874 UR - https://www.unboundmedicine.com/medline/citation/30170993/Identification_of_a_functional_FADS1_3'UTR_variant_associated_with_erythrocyte_n_6_polyunsaturated_fatty_acids_levels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1933-2874(18)30352-0 DB - PRIME DP - Unbound Medicine ER -