BACKGROUND: Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. METHODS: SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. RESULTS: Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E-5), lower delta-5 desaturase enzyme activity (p = 2.09E-9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. CONCLUSION: This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression.

Department of Human Biology NUTRIM School for Nutrition and Translational Research in Metabolism Maastricht University Medical Centre Maastricht The Netherlands

Department of Human Health and Nutritional Sciences University of Guelph Guelph ON N1G 2W1 Canada

Department of Nutrition Exercise and Sports University of Copenhagen Copenhagen Denmark

Institut National de la Santé et de la Recherche Médicale Institute of Metabolic and Cardiovascular Diseases UMR1048 Toulouse France

Institute of Endocrinology Obesity Management Centre Prague Czech Republic

Institute of Metabolic and Cardiovascular Diseases University of Toulouse Paul Sabatier University UMR1048 Toulouse France

Laboratory of Clinical Biochemistry Toulouse University Hospitals Toulouse France

Nestlé Institute of Health Sciences Department of Nutrition and Metabolic Health Lausanne Switzerland

Zobrazit více v PubMed

Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinol. 2018;14:12–24. DOI

Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017;13:633–43. DOI

Ralston JC, Lyons CL, Kennedy EB, Kirwan AM, Roche HM. Fatty acids and NLRP3 inflammasome-mediated inflammation in metabolic tissues. Annu Rev Nutr. 2017;37:77–102. DOI

Siriwardhana N, Kalupahana NS, Cekanova M, LeMieux M, Greer B, Moustaid-Moussa N. Modulation of adipose tissue inflammation by bioactive food compounds. J Nutr Biochem. 2013;24:613–23. DOI

Marion-Letellier R, Savoye G, Ghosh S. Polyunsaturated fatty acids and inflammation. IUBMB Life. 2015;67:659–67. DOI

Nakamura MT, Nara TY. Structure, function, and dietary regulation ofdelta6, delta5, and delta9 desaturases. Annu Rev Nutr. 2004;24:345–76. DOI

Ralston JC, Matravadia S, Gaudio N, Holloway GP, Mutch DM. Polyunsaturated fatty acid regulation of adipocyte FADS1 and FADS2 expression and function. Obesity (Silver Spring). 2015;23:725–8. DOI

Harris C, Demmelmair H, von Berg A, Lehmann I, Flexeder C, Koletzko B, et al. Associations between fatty acids and low-grade inflammation in children from the LISAplus birth cohort study. Eur J Clin Nutr. 2017;71:1303–11. DOI

Roke K, Ralston JC, Abdelmagid S, Nielsen DE, Badawi A, El-Sohemy A, et al. Variation in the FADS1/2 gene cluster alters plasma n-6 PUFA and is weakly associated with hsCRP levels in healthy young adults. Prostaglandins Leukot Essent Fatty Acids. 2013;89:257–63. DOI

Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, Trabetti E, et al. FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr. 2008;88:941–9. DOI

Vaittinen M, Walle P, Kuosmanen E, Mannisto V, Kakela P, Agren J, et al. FADS2 genotype regulates delta-6 desaturase activity and inflammation in human adipose tissue. J Lipid Res. 2016;57:56–65. DOI

Merino DM, Ma DW, Mutch DM. Genetic variation in lipid desaturases and its impact on the development of human disease. Lipids Health Dis. 2010;9:63. DOI

O’Neill CM, Minihane AM. The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults. Proc Nutr Soc. 2017;76:64–75. DOI

Tosi F, Sartori F, Guarini P, Olivieri O, Martinelli N. Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease. Adv Exp Med Biol. 2014;824:61–81. DOI

Hester AG, Murphy RC, Uhlson CJ, Ivester P, Lee TC, Sergeant S, et al. Relationship between a common variant in the fatty acid desaturase (FADS) cluster and eicosanoid generation in humans. J Biol Chem. 2014;289:22482–9. DOI

Larsen TM, Dalskov S, van Baak M, Jebb S, Kafatos A, Pfeiffer A, et al. The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries - a comprehensive design for long-term intervention. Obes Rev. 2010;11:76–91. DOI

Kunesova M, Hlavaty P, Tvrzicka E, Stankova B, Kalouskova P, Viguerie N, et al. Fatty acid composition of adipose tissue triglycerides after weight loss and weight maintenance: the DIOGENES study. Physiol Res. 2012;61:597–607. PubMed PMC

Zhao L, Ni Y, Ma X, Zhao A, Bao Y, Liu J, et al. A panel of free fatty acid ratios to predict the development of metabolic abnormalities in healthy obese individuals. Sci Rep. 2016;6:28418. DOI

Viguerie N, Montastier E, Maoret JJ, Roussel B, Combes M, Valle C, et al. Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation. PLoS Genet. 2012;8:e1002959. DOI

Carayol J, Chabert C, Di Cara A, Armenise C, Lefebvre G, Langin D, et al. Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator. Nat Commun. 2017;8:2084. DOI

Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PI. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008;24:2938–9. DOI

Tanaka T, Shen J, Abecasis GR, Kisialiou A, Ordovas JM, Guralnik JM, et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet. 2009;5:e1000338. DOI

Kwak JH, Paik JK, Kim OY, Jang Y, Lee SH, Ordovas JM, et al. FADS gene polymorphisms in Koreans: association with omega6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease. Atherosclerosis. 2011;214:94–100. DOI

Sergeant S, Hugenschmidt CE, Rudock ME, Ziegler JT, Ivester P, Ainsworth HC, et al. Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome. Br J Nutr. 2012;107:547–55. DOI

Lê Cao KA, González I, Déjean S. integrOmics: an R package to unravel relationships between two omics data sets. Bioinformatics. 2009;25:2855–6. DOI

Vaittinen M, Mannisto V, Kakela P, Agren J, Tiainen M, Schwab U, et al. Interorgan cross talk between fatty acid metabolism, tissue inflammation, and FADS2 genotype in humans with obesity. Obesity (Silver Spring). 2017;25:545–52. DOI

Aslibekyan S, Jensen MK, Campos H, Linkletter CD, Loucks EB, Ordovas JM, et al. Fatty acid desaturase gene variants, cardiovascular risk factors, and myocardial infarction in the Costa Rica study. Front Genet. 2012;3:72. DOI

Rahbar E, Ainsworth HC, Howard TD, Hawkins GA, Ruczinski I, Mathias R, et al. Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster. PLoS ONE. 2017;12:e0180903. DOI

Yashiro H, Takagahara S, Tamura YO, Miyahisa I, Matsui J, Suzuki H, et al. A novel selective inhibitor of delta-5 desaturase lowers insulin resistance and reduces body weight in diet-induced obese C57BL/6J mice. PLoS ONE. 2016;11:e0166198. DOI

Sergeant S, Rahbar E, Chilton FH. Gamma-linolenic acid, dihommo-gamma linolenic, eicosanoids and inflammatory processes. Eur J Pharmacol. 2016;785:77–86. DOI

The fatty acid composition of serum phospholipids in adolescents is associated with body composition in early adulthoods: an eight-year follow-up study