Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway
Year: 2013
Type: article
Study design: Observational Study
Abstract: BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
Authors: Jason H.Y. Wu, Rozenn N. Lemaitre, Ani Manichaikul, Weihua Guan, Toshiko Tanaka, Millennia Foy, Edmond K. Kabagambe, Luc Djousse, David Siscovick, Amanda M. Fretts, Catherine Johnson, Irena B. King, Bruce M. Psaty, Barbara McKnight, Stephen S. Rich, Yii-Der I. Chen, Jennifer A. Nettleton, Weihong Tang, Stefania Bandinelli, David R. Jacobs, Brian L. Browning, Cathy C. Laurie, Xiangjun Gu, Michael Y. Tsai, Lyn M. Steffen, Luigi Ferrucci, Myriam Fornage, Dariush Mozaffarian
Institutions: Harvard University, The University of Western Australia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Hjartavernd, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities
Awards: CARDIA, G1052397333, G1135917780, Multi-Ethnic Study of Atherosclerosis (MESA) Study, G1220223050, G1241292848, G1243299691, G1261793039, G1409423729, G1527150935, CARDIA, CORONARY HEART DISEASE AND STROKE, G1639455850, CARDIA, G1691174148, MESA Family Study - Columbia University Field Center, UCLA Clinical and Translational Science Institute, G1727292203, G173303992, G191650467, G1941623656, CARDIA-ECHOCARDIOGRAPHY READING, G2194386449, G236442059, Clinical and Translational Science Award, Institute for Clinical and Translational Research (UL1), CARDIA, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), MESA Family Study, G261675466, G262043649, G2663518188, G277826483, G2786045897, G2800149121, G2818629771, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, LONGITUDINAL STUDIES OF CORONARY HEART DISEASE RISK FACTORS IN YOUNG ADULTS, G3107571658, G3114902838, CORONARY ARTERY DISEASE RISK DEVELOPMENT IN YOUNG ADULTS, G3226848658, UCLA Clinical and Translational Science Institute, MESA Family Study, G3396487927, G3410686264, G3444966432, G3462919067, G3647016462, G36937976, GWA for Gene-Environment Interaction Effects Influencing CHD, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Predictors of Alheimers Disease in Mild Cognitive Impairment, G4139317420, G4165892905, G423252844, Coronary Artery Risk Development in Young Adults (CARDIA) Study - Field Center, Subcortical Hyperintensities in Sleep Apnea Syndrome, G457330776, Genome Wide Association Coordinating Center, MESA Family Study, CARDIA, MESA Family Study, G50822097, G510023084, GWAS of longitudinal blood pressure profiles from young adulthood to middle-age, A Center for GEI Association Studies, G5232982263, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5452216648, Epidemiology of Venous Thrombosis and Pulmonary Embolism, G567847597, G573134505, G582705428, CHARGE consortium: omics discovery for CVD and aging phenotypes, CHS Events Follow-up Study, G616491540, G6226795708, Predictors of Alzheimers Disease in Mild Cognitive Impairment, G6520056932, G6548750934, CHS-Transition Phase, G715477388, Interaction between diet and genetic variation: influence on Type 2 Diabetes risk, MESA Family Study, Improving genotype call accuracy, MESA, Circulating Dietary & Metabolic Fatty Acids, Major CVD Outcomes, & Healthy Aging, CHS RETINAL READING CENTER, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), G777822606, CHS Events Follow-up Study, G7999488110, COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA, Genes of the CYP450-Derived Eicosanoids Pathway in Subclinical Atherosclerosis, HISPANIC SECONDARY STROKE PREVENTION INITIATIVE, Hormonal trajectories in aging, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, G905887895, G991334795
OpenAlex ID: W1973631566