title: Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders.
abstract: Fatty acids (FAs) are involved in cellular processes important for normal body function, and perturbation of FA balance has been linked to metabolic disturbances, including type 2 diabetes. An individual's level of FAs is affected by diet, lifestyle, and genetic variation. We aimed to improve the understanding of the mechanisms and pathways involved in regulation of FA tissue levels, by identifying genetic loci associated with inter-individual differences in erythrocyte membrane FA levels. We assessed the levels of 22 FAs in the phospholipid fraction of erythrocyte membranes from 2,626 Greenlanders in relation to single nucleotide polymorphisms genotyped on the MetaboChip or imputed. We identified six independent association signals. Novel loci were identified on chromosomes 5 and 11 showing strongest association with oleic acid (rs76430747 in ACSL6, beta (SE): -0.386% (0.034), p = 1.8x10-28) and docosahexaenoic acid (rs6035106 in DTD1, 0.137% (0.025), p = 6.4x10-8), respectively. For a missense variant (rs80356779) in CPT1A, we identified a number of novel FA associations, the strongest with 11-eicosenoic acid (0.473% (0.035), p = 2.6x10-38), and for variants in FADS2 (rs174570), LPCAT3 (rs2110073), and CERS4 (rs11881630) we replicated known FA associations. Moreover, we observed metabolic implications of the ACSL6 (rs76430747) and CPT1A (rs80356779) variants, which both were associated with altered HbA1c (0.051% (0.013), p = 5.6x10-6 and -0.034% (0.016), p = 3.1x10-4, respectively). The latter variant was also associated with reduced insulin resistance (HOMA-IR, -0.193 (0.050), p = 3.8x10-6), as well as measures of smaller body size, including weight (-2.676 kg (0.523), p = 2.4x10-7), lean mass (-1.200 kg (0.271), p = 1.7x10-6), height (-0.966 cm (0.230), p = 2.0x10-5), and BMI (-0.638 kg/m2 (0.181), p = 2.8x10-4). In conclusion, we have identified novel genetic determinants of FA composition in phospholipids in erythrocyte membranes, and have shown examples of links between genetic variants associated with altered FA membrane levels and changes in metabolic traits.
authors.affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette Korre
authors.initials: MK
authors.lastname: Andersen
authors.affiliation: The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Emil
authors.identifier: 0000-0002-0593-7906
authors.initials: E
authors.lastname: Jørsboe
authors.affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Camilla Helene
authors.initials: CH
authors.lastname: Sandholt
authors.affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Marit Eika
authors.initials: ME
authors.lastname: Jørgensen
authors.affiliation: Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Nils Joakim
authors.initials: NJ
authors.lastname: Færgeman
authors.affiliation: National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.|Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.
authors.forename: Peter
authors.initials: P
authors.lastname: Bjerregaard
authors.affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Moltke
authors.affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
mesh_terms: D049628:Body Size / Q000235:genetics; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D003066:Coenzyme A Ligases / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000235:genetics; D004910:Erythrocyte Membrane / Q000235:genetics*; D005227:Fatty Acids / Q000235:genetics*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D005838:Genotype; D006442:Glycated Hemoglobin / Q000235:genetics; D006116:Greenland; D006801:Humans; D007328:Insulin / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D019301:Oleic Acid / Q000235:genetics; D010743:Phospholipids / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D002334:Carnitine O-Palmitoyltransferase; D003066:Coenzyme A Ligases; D004281:Docosahexaenoic Acids; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D006442:Glycated Hemoglobin; D007328:Insulin; D019301:Oleic Acid; D010743:Phospholipids; C517652:hemoglobin A1c protein, human; C577474:CPT1A protein, human; C403665:ACSL6 protein, human; C572289:eicosenoic acid