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Insertion-deletions in a FADS2 intron 1 conserved regulatory locus control expression of fatty acid desaturases 1 and 2 and modulate response to simvastatin.

Abstract

The fatty acid desaturase genes (FADS1 and FADS2) code for enzymes required for synthesis of omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFA) important in the central nervous system, inflammatory response, and cardiovascular health. SNPs in these genes are associated with numerous health outcomes, but it is unclear how genetic variation affects enzyme function. Here, lymphoblasts obtained from Japanese participants in the International HapMap Project were evaluated for association of expression microarray results with SNPs in the FADS gene cluster. Six SNPs in the first intron of the FADS2 gene were associated with FADS1 expression. A 10-SNP haplotype in FADS2 (rs2727270 to rs2851682) present in 24% of the population was associated with lower expression of FADS1. A highly conserved region coinciding with the most significant SNPs contained predicted binding sites for SREBP and PPARγ. Lymphoblasts homozygous for either the major or minor haplotype were treated with agonists for these transcription factors and expression of FADS1 and FADS2 determined. Simvastatin and the LXR agonist GW3965 both upregulated expression of FADS1 and FADS2; no response was found for PPARγ agonist rosiglitazone. The minor haplotype homozygotes had 20-40% higher induction of FADS1 and FADS2 after simvastatin or GW3965 treatment. A 22 bp polymorphic insertion-deletion (INDEL) was found 137 bp downstream from the putative sterol response element, as well as a 3 or 1 bp INDEL 81-83 bp downstream. All carriers of the minor haplotype had deletions while all carriers of the major haplotype had insertions. Individuals carrying the minor haplotype may be vulnerable to alterations in diet that reduce LCPUFA intake, and especially responsive to statin or marine oil therapy.

Authors+Show Affiliations

Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22748975

Citation

Reardon, Holly T., et al. "Insertion-deletions in a FADS2 Intron 1 Conserved Regulatory Locus Control Expression of Fatty Acid Desaturases 1 and 2 and Modulate Response to Simvastatin." Prostaglandins, Leukotrienes, and Essential Fatty Acids, vol. 87, no. 1, 2012, pp. 25-33.
Reardon HT, Zhang J, Kothapalli KS, et al. Insertion-deletions in a FADS2 intron 1 conserved regulatory locus control expression of fatty acid desaturases 1 and 2 and modulate response to simvastatin. Prostaglandins Leukot Essent Fatty Acids. 2012;87(1):25-33.
Reardon, H. T., Zhang, J., Kothapalli, K. S., Kim, A. J., Park, W. J., & Brenna, J. T. (2012). Insertion-deletions in a FADS2 intron 1 conserved regulatory locus control expression of fatty acid desaturases 1 and 2 and modulate response to simvastatin. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 87(1), 25-33. https://doi.org/10.1016/j.plefa.2012.04.011
Reardon HT, et al. Insertion-deletions in a FADS2 Intron 1 Conserved Regulatory Locus Control Expression of Fatty Acid Desaturases 1 and 2 and Modulate Response to Simvastatin. Prostaglandins Leukot Essent Fatty Acids. 2012;87(1):25-33. PubMed PMID: 22748975.
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TY - JOUR T1 - Insertion-deletions in a FADS2 intron 1 conserved regulatory locus control expression of fatty acid desaturases 1 and 2 and modulate response to simvastatin. AU - Reardon,Holly T, AU - Zhang,Jimmy, AU - Kothapalli,Kumar S D, AU - Kim,Andrea J, AU - Park,Woo Jung, AU - Brenna,J Thomas, Y1 - 2012/06/27/ PY - 2012/04/27/received PY - 2012/04/30/accepted PY - 2012/7/4/entrez PY - 2012/7/4/pubmed PY - 2013/1/23/medline SP - 25 EP - 33 JF - Prostaglandins, leukotrienes, and essential fatty acids JO - Prostaglandins Leukot. Essent. Fatty Acids VL - 87 IS - 1 N2 - The fatty acid desaturase genes (FADS1 and FADS2) code for enzymes required for synthesis of omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFA) important in the central nervous system, inflammatory response, and cardiovascular health. SNPs in these genes are associated with numerous health outcomes, but it is unclear how genetic variation affects enzyme function. Here, lymphoblasts obtained from Japanese participants in the International HapMap Project were evaluated for association of expression microarray results with SNPs in the FADS gene cluster. Six SNPs in the first intron of the FADS2 gene were associated with FADS1 expression. A 10-SNP haplotype in FADS2 (rs2727270 to rs2851682) present in 24% of the population was associated with lower expression of FADS1. A highly conserved region coinciding with the most significant SNPs contained predicted binding sites for SREBP and PPARγ. Lymphoblasts homozygous for either the major or minor haplotype were treated with agonists for these transcription factors and expression of FADS1 and FADS2 determined. Simvastatin and the LXR agonist GW3965 both upregulated expression of FADS1 and FADS2; no response was found for PPARγ agonist rosiglitazone. The minor haplotype homozygotes had 20-40% higher induction of FADS1 and FADS2 after simvastatin or GW3965 treatment. A 22 bp polymorphic insertion-deletion (INDEL) was found 137 bp downstream from the putative sterol response element, as well as a 3 or 1 bp INDEL 81-83 bp downstream. All carriers of the minor haplotype had deletions while all carriers of the major haplotype had insertions. Individuals carrying the minor haplotype may be vulnerable to alterations in diet that reduce LCPUFA intake, and especially responsive to statin or marine oil therapy. SN - 1532-2823 UR - https://www.unboundmedicine.com/medline/citation/22748975/Insertion_deletions_in_a_FADS2_intron_1_conserved_regulatory_locus_control_expression_of_fatty_acid_desaturases_1_and_2_and_modulate_response_to_simvastatin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0952-3278(12)00066-X DB - PRIME DP - Unbound Medicine ER -