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A fatty acid desaturase expression quantitative trait locus modulates response to simvastatin
Author(s) -
Reardon Holly T.,
Zhang Jimmy,
Kothapalli Kumar S.D.,
Kim Andrea J.,
Park Woo Jung,
Brenna J. Thomas
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.242.2
Subject(s) - fads2 , single nucleotide polymorphism , haplotype , genetics , biology , minor allele frequency , population , snp , gene , polyunsaturated fatty acid , fatty acid , medicine , allele , genotype , biochemistry , docosahexaenoic acid , environmental health
The FADS1 and FADS2 genes encode fatty acid desaturases required for synthesis of omega‐3 and omega‐6 long‐chain polyunsaturated fatty acids (LCPUFA) important in cardiovascular health. Single nucleotide polymorphisms (SNPs) in these genes are associated with many health outcomes, but mechanisms are unclear. Here, lymphoblast expression microarray results from Japanese in Tokyo International HapMap participants were associated with SNPs in the FADS gene cluster. A 10‐SNP haplotype in FADS2 present in 24% of the population was significantly associated with lower FADS1 expression. A highly conserved region coinciding with the most significant SNPs contained predicted binding sites for PPARγ and SREBP. Lymphoblasts homozygous for the major or minor haplotype were treated with agonists for these transcription factors. Minor haplotype homozygotes had 20–40% higher induction of FADS1 and FADS2 after treatment with the statin drug simvastatin or LXR agonist GW3965, suggesting enhanced responsiveness to SREBP‐1c. Sequencing of the region identified two deletion mutations within 150 bp of the putative sterol response element in minor haplotype carriers. Individuals carrying these deletions may be particularly vulnerable to low dietary LCPUFA, and may be especially responsive to statin or marine oil therapy. SUPPORT: Grant# T32HD052471 from the National Institutes of Child Health and Human Development.