title: Relationship between a common variant in the fatty acid desaturase (FADS) cluster and eicosanoid generation in humans.
abstract: Dramatic shifts in the Western diet have led to a marked increase in the dietary intake of the n-6 polyunsaturated fatty acid (PUFA), linoleic acid (LA). Dietary LA can then be converted to arachidonic acid (ARA) utilizing three enzymatic steps. Two of these steps are encoded for by the fatty acid desaturase (FADS) cluster (chromosome 11, 11q12.2-q13) and certain genetic variants within the cluster are highly associated with ARA levels. However, no study to date has examined whether these variants further influence pro-inflammatory, cyclooxygenase and lipoxygenase eicosanoid products. This study examined the impact of a highly influential FADS SNP, rs174537 on leukotriene, HETE, prostaglandin, and thromboxane biosynthesis in stimulated whole blood. Thirty subjects were genotyped at rs174537 (GG, n = 11; GT, n = 13; TT, n = 6), a panel of fatty acids from whole serum was analyzed, and precursor-to-product PUFA ratios were calculated as a marker of the capacity of tissues (particularly the liver) to synthesize long chain PUFAs. Eicosanoids produced by stimulated human blood were measured by LC-MS/MS. We observed an association between rs174537 and the ratio of ARA/LA, leukotriene B4, and 5-HETE but no effect on levels of cyclooxygenase products. Our results suggest that variation at rs174537 not only impacts the synthesis of ARA but the overall capacity of whole blood to synthesize 5-lipoxygenase products; these genotype-related changes in eicosanoid levels could have important implications in a variety of inflammatory diseases.
authors: From the Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors: Austin G
authors: AG
authors: Hester
authors: the Department of Pharmacology, University of Colorado Denver, Aurora, Colorado 80045.
authors: Robert C
authors: RC
authors: Murphy
authors: the Department of Pharmacology, University of Colorado Denver, Aurora, Colorado 80045.
authors: Charis J
authors: CJ
authors: Uhlson
authors: the Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors: Priscilla
authors: P
authors: Ivester
authors: the Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors: Tammy C
authors: TC
authors: Lee
authors: the Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors: Susan
authors: S
authors: Sergeant
authors: the Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors: Leslie R
authors: LR
authors: Miller
authors: the Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors: Timothy D
authors: TD
authors: Howard
authors: the Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21224, and.
authors: Rasika A
authors: RA
authors: Mathias
authors: the Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the Molecular Medicine and Translation Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 schilton@wakehealth.edu.
authors: Floyd H
authors: FH
authors: Chilton
mesh_terms: D000328:Adult; D016718:Arachidonic Acid / Q000097:blood / Q000378:metabolism; D000090943:Delta-5 Fatty Acid Desaturase; D066273:Diet, Western / Q000009:adverse effects; D015777:Eicosanoids / Q000096:biosynthesis* / Q000097:blood; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D019787:Linoleic Acid / Q000097:blood / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D015777:Eicosanoids; D018836:Inflammation Mediators; D007975:Leukotriene B4; D016718:Arachidonic Acid; D019787:Linoleic Acid; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human
keywords: Arachidonic Acid (AA) (ARA); Eicosanoid; Fatty Acid Desaturase; Inflammation; Nutrition; Polyunsaturated Fatty Acid (PUFA); Single-nucleotide Polymorphism (SNP)