Novel Genetic Loci Associated with the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation

Background: A recent genome-wide association study (GWAS) by our group identified 13 loci associated with the plasma triglyceride (TG) response to omega-3 (n-3) fatty acid (FA) supplementation. This study aimed to test whether single-nucleotide polymorphisms (SNPs) within the IQCJ, NXPH1, PHF17 and MYB genes are associated with the plasma TG response to an n-3 FA supplementation. Methods: A total of 208 subjects followed a 6-week n-3 FA supplementation of 5 g/day of fish oil (1.9-2.2 g of eicosapentaenoic acid and 1.1 g of docosahexaenoic acid). Measurements of plasma lipids were made before and after the supplementation. Sixty-seven tagged SNPs were selected to increase the density of markers near GWAS hits. Results: In a repeated model, independent effects of the genotype and the gene-supplementation interaction were associated with plasma TG. Genotype effects were observed with two SNPs of NXPH1, and gene-diet interactions were observed with ten SNPs of IQCJ, four SNPs of NXPH1 and three SNPs of MYB. Positive and negative responders showed different genotype frequencies with nine SNPs of IQCJ, two SNPs of NXPH1 and two SNPs of MYB. Conclusion: Fine mapping in GWAS-associated loci allowed the identification of SNPs partly explaining the large interindividual variability observed in plasma TG levels in response to an n-3 FA supplementation.

[1]  I. Borecki,et al.  Genetic Analysis of 16 NMR-Lipoprotein Fractions in Humans, the GOLDN Study , 2013, Lipids.

[2]  M. Inouye,et al.  Transcriptional regulation of the human NaPi-IIb cotransporter by EGF in Caco-2 cells involves c-myb. , 2003, American journal of physiology. Cell physiology.

[3]  B. Lambrecht,et al.  In vitro human embryonic stem cell hematopoiesis mimics MYB-independent yolk sac hematopoiesis , 2015, Haematologica.

[4]  M. Vohl,et al.  Association between Polymorphisms in the Fatty Acid Desaturase Gene Cluster and the Plasma Triacylglycerol Response to an n-3 PUFA Supplementation , 2012, Nutrients.

[5]  P. Calder,et al.  Genome-wide association study of the plasma triglyceride response to an n-3 polyunsaturated fatty acid supplementation[S] , 2014, Journal of Lipid Research.

[6]  P. Calder,et al.  Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study. , 2008, The American journal of clinical nutrition.

[7]  Liang Zhao,et al.  The MYB proto-oncogene suppresses monocytic differentiation of acute myeloid leukemia cells via transcriptional activation of its target gene GFI1 , 2014, Oncogene.

[8]  I. Dominguez,et al.  Cell cycle-dependent chromatin shuttling of HBO1–JADE1 histone acetyl transferase (HAT) complex , 2014, Cell cycle.

[9]  Richard A. Gibbs,et al.  Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population , 2012, PloS one.

[10]  Moshe Levi,et al.  Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. , 2011, Circulation.

[11]  B. Staels,et al.  Peroxisome proliferator-activated receptors in inflammation control. , 2001, The Journal of endocrinology.

[12]  M. Vohl,et al.  Effects of Age, Sex, Body Mass Index and APOE Genotype on Cardiovascular Biomarker Response to an n-3 Polyunsaturated Fatty Acid Supplementation , 2013, Lifestyle Genomics.

[13]  M. Missler,et al.  Dystroglycan Binding to α-Neurexin Competes with Neurexophilin-1 and Neuroligin in the Brain* , 2014, The Journal of Biological Chemistry.

[14]  Hong Xu,et al.  Overexpression of the c-Myb but not its leukemogenic mutant DNA-binding domain increased adipogenic differentiation in mesenchymal stem cells. , 2011, Biochemical and biophysical research communications.

[15]  Wai Keung Christopher Lai,et al.  Homocysteine-Induced Endothelial Dysfunction , 2015, Annals of Nutrition and Metabolism.

[16]  D. Kiefer,et al.  Omega-3 fatty acids: An update emphasizing clinical use. , 2012, Agro food industry hi-tech.

[17]  E. Schaefer,et al.  Automated enzymatic standardized lipid analyses for plasma and lipoprotein fractions. , 1987, Clinica chimica acta; international journal of clinical chemistry.

[18]  S. Scherer,et al.  IQCJ-SCHIP1, a novel fusion transcript encoding a calmodulin-binding IQ motif protein. , 2006, Biochemical and biophysical research communications.

[19]  M. Laakso,et al.  Impact of the Pro12Ala polymorphism of the PPAR-gamma2 gene on serum triacylglycerol response to n-3 fatty acid supplementation. , 2003, Molecular genetics and metabolism.

[20]  J. Girault,et al.  Schwannomin-Interacting Protein-1 Isoform IQCJ-SCHIP-1 Is a Late Component of Nodes of Ranvier and Axon Initial Segments , 2008, The Journal of Neuroscience.

[21]  Lawrence A Leiter,et al.  Lipid‐altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials , 2011, Diabetes, obesity & metabolism.

[22]  T. Südhof,et al.  Neurexophilin binding to alpha-neurexins. A single LNS domain functions as an independently folding ligand-binding unit. , 1998, The Journal of biological chemistry.

[23]  M. Burstein,et al.  [On a rapid determination of the cholesterol bound to the serum alpha- and beta-lipoproteins]. , 1960, Clinica chimica acta; international journal of clinical chemistry.

[24]  J. Brehm,et al.  Analyses of shared genetic factors between asthma and obesity in children. , 2010, The Journal of allergy and clinical immunology.

[25]  M. V. Panchenko,et al.  Jade-1, a candidate renal tumor suppressor that promotes apoptosis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  P. Marik,et al.  Omega‐3 Dietary Supplements and the Risk of Cardiovascular Events: A Systematic Review , 2009, Clinical cardiology.

[27]  I. Borecki,et al.  Genome-wide association study indicates variants associated with insulin signaling and inflammation mediate lipoprotein responses to fenofibrate , 2012, Pharmacogenetics and genomics.

[28]  J. Saver,et al.  Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. , 2011, Atherosclerosis.

[29]  C. Vaziri,et al.  Role of Jade-1 in the Histone Acetyltransferase (HAT) HBO1 Complex*♦ , 2008, Journal of Biological Chemistry.

[30]  P. Wilson,et al.  Association Between the PPARA L162V Polymorphism and Plasma Lipid Levels: The Framingham Offspring Study , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[31]  P. Talmud,et al.  ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[32]  P. Rodriguez,et al.  Role of c‐Myb in the survival of pre B‐cell acute lymphoblastic leukemia and leukemogenesis , 2012, American journal of hematology.

[33]  M. Bragt,et al.  Comparison of the effects of n-3 long chain polyunsaturated fatty acids and fenofibrate on markers of inflammation and vascular function, and on the serum lipoprotein profile in overweight and obese subjects. , 2012, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[34]  T. Südhof,et al.  Neurexophilins Form a Conserved Family of Neuropeptide-Like Glycoproteins , 1998, The Journal of Neuroscience.

[35]  M. Hermsen,et al.  Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression , 2014, Laboratory Investigation.

[36]  M. Maekawa,et al.  Relationship between triglyceride concentrations and LDL size evaluated by malondialdehyde-modified LDL. , 2001, Clinical chemistry.

[37]  Song Tan,et al.  ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. , 2006, Molecular cell.

[38]  A. Avenell,et al.  Genetic variation and the lipid response to dietary intervention: a systematic review. , 2003, The American journal of clinical nutrition.