Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders
Disruption of fatty-acid balance has in several previous studies been linked to human health conditions, including the metabolic syndrome, type 2 diabetes, and insulin resistance. Composition of fatty acids in lipid membranes is influenced, not only by diet and lifestyle, but also by genetic variation. By identifying genes linked to changes in the level of specific fatty acids, it may be possible to identify biological mechanisms and pathways central to regulation of fatty-acid composition in lipid membranes. We therefore aimed at finding such genes by studying Greenlanders. We identified six genomic regions harboring variants, which were associated with the level of at least one of 22 assessed erythrocyte membrane fatty acids, including two novel regions not previously linked to fatty acid levels. Moreover, we showed that two of the identified variants were associated with altered levels of glycosylated hemoglobin, and one of these variants was associated with reduced insulin resistance and decreased measures of body size. These results contribute to our understanding of fatty acid metabolism, and support a link between fatty acid balance and metabolic health.
Vyšlo v časopise:
Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders. PLoS Genet 12(6): e32767. doi:10.1371/journal.pgen.1006119
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1006119
Souhrn
Disruption of fatty-acid balance has in several previous studies been linked to human health conditions, including the metabolic syndrome, type 2 diabetes, and insulin resistance. Composition of fatty acids in lipid membranes is influenced, not only by diet and lifestyle, but also by genetic variation. By identifying genes linked to changes in the level of specific fatty acids, it may be possible to identify biological mechanisms and pathways central to regulation of fatty-acid composition in lipid membranes. We therefore aimed at finding such genes by studying Greenlanders. We identified six genomic regions harboring variants, which were associated with the level of at least one of 22 assessed erythrocyte membrane fatty acids, including two novel regions not previously linked to fatty acid levels. Moreover, we showed that two of the identified variants were associated with altered levels of glycosylated hemoglobin, and one of these variants was associated with reduced insulin resistance and decreased measures of body size. These results contribute to our understanding of fatty acid metabolism, and support a link between fatty acid balance and metabolic health.
Zdroje
1. Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274: 1363–1367. 7563561
2. Lemaitre RN, King IB, Mozaffarian D, Sotoodehnia N, Rea TD, Kuller LH, et al. Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study. Circulation. 2006;114: 209–215. doi: 10.1161/CIRCULATIONAHA.106.620336 16818809
3. Sun Q, Ma J, Campos H, Rexrode KM, Albert CM, Mozaffarian D, et al. Blood concentrations of individual long-chain n-3 fatty acids and risk of nonfatal myocardial infarction. Am J Clin Nutr. 2008;88: 216–223. 18614744
4. Yamagishi K, Folsom AR, Steffen LM. Plasma fatty acid composition and incident ischemic stroke in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Cerebrovasc Dis. 2013;36: 38–46. doi: 10.1159/000351205 23920478
5. Sala-Vila A, Cofan M, Perez-Heras A, Nunez I, Gilabert R, Junyent M, et al. Fatty acids in serum phospholipids and carotid intima-media thickness in Spanish subjects with primary dyslipidemia. Am J Clin Nutr. 2010;92: 186–193. doi: 10.3945/ajcn.2009.28807 20463042
6. Simon JA, Hodgkins ML, Browner WS, Neuhaus JM, Bernert JT, Hulley SB. Serum fatty acids and the risk of coronary heart disease. Am J Epidemiol. 1995;142: 469–476. 7677125
7. Friedberg CE, Janssen MJ, Heine RJ, Grobbee DE. Fish oil and glycemic control in diabetes. A meta-analysis. Diabetes Care. 1998;21: 494–500. 9571330
8. Wang L, Folsom AR, Zheng Z-J, Pankow JS, Eckfeldt JH. Plasma fatty acid composition and incidence of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr. 2003;78: 91–98. 12816776
9. Warensjö E, Sundström J, Lind L, Vessby B. Factor analysis of fatty acids in serum lipids as a measure of dietary fat quality in relation to the metabolic syndrome in men. Am J Clin Nutr. 2006;84: 442–448. 16895896
10. Poudyal H, Brown L. Should the pharmacological actions of dietary fatty acids in cardiometabolic disorders be classified based on biological or chemical function? Prog Lipid Res. 2015;59: 172–200. doi: 10.1016/j.plipres.2015.07.002 26205317
11. Sun Q, Ma J, Campos H, Hankinson SE, Manson JE, Stampfer MJ, et al. A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease. Circulation. 2007;115: 1858–1865. doi: 10.1161/CIRCULATIONAHA.106.679985 17389261
12. Sun Q, Ma J, Campos H, Hankinson SE, Hu FB. Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women. Am J Clin Nutr. 2007;86: 74–81. 17616765
13. Jacobs S, Schiller K, Jansen E, Fritsche A, Weikert C, di Giuseppe R, et al. Association between erythrocyte membrane fatty acids and biomarkers of dyslipidemia in the EPIC-Potsdam study. Eur J Clin Nutr. 2014;68: 517–525. doi: 10.1038/ejcn.2014.18 24569539
14. Kunesová M, Hainer V, Tvrzicka E, Phinney SD, Stich V, Parízková J, et al. Assessment of dietary and genetic factors influencing serum and adipose fatty acid composition in obese female identical twins. Lipids. 2002;37: 27–32. 11876260
15. Kunesová M, Phinney S, Hainer V, Tvrzická E, Stich V, Parízková J, et al. The responses of serum and adipose Fatty acids to a one-year weight reduction regimen in female obese monozygotic twins. Ann N Y Acad Sci. 2002;967: 311–323. 12079858
16. Lemaitre RN, Siscovick DS, Berry EM, Kark JD, Friedlander Y. Familial aggregation of red blood cell membrane fatty acid composition: the Kibbutzim Family Study. Metabolism. 2008;57: 662–668. doi: 10.1016/j.metabol.2007.12.011 18442630
17. Harris WS, Pottala J V, Lacey SM, Vasan RS, Larson MG, Robins SJ. Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study. Atherosclerosis. 2012;225: 425–431. doi: 10.1016/j.atherosclerosis.2012.05.030 22727409
18. Moltke I, Fumagalli M, Korneliussen TS, Crawford JE, Bjerregaard P, Jørgensen ME, et al. Uncovering the Genetic History of the Present-Day Greenlandic Population. Am J Hum Genet. The American Society of Human Genetics; 2015;96: 54–69. doi: 10.1016/j.ajhg.2014.11.012
19. Moltke I, Grarup N, Jørgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature. Nature Publishing Group; 2014;512: 190–193. doi: 10.1038/nature13425
20. Jeppesen C, Jørgensen ME, Bjerregaard P. Assessment of consumption of marine food in Greenland by a food frequency questionnaire and biomarkers. Int J Circumpolar Health. 2012;71: 18361. doi: 10.3402/ijch.v71i0.18361 22663940
21. Fumagalli M, Moltke I, Grarup N, Racimo F, Bjerregaard P, Jorgensen ME, et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science. 2015;349: 1343–1347. doi: 10.1126/science.aab2319 26383953
22. Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med (Maywood). 2008;233: 507–521. doi: 10.3181/0710-MR-287
23. Grevengoed TJ, Klett EL, Coleman RA. Acyl-CoA metabolism and partitioning. Annu Rev Nutr. 2014;34: 1–30. doi: 10.1146/annurev-nutr-071813-105541 24819326
24. Fujino T, Yamamoto T. Cloning and functional expression of a novel long-chain acyl-CoA synthetase expressed in brain. J Biochem. 1992;111: 197–203. 1569043
25. Jakobsson A, Westerberg R, Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res. 2006;45: 237–249. doi: 10.1016/j.plipres.2006.01.004 16564093
26. Marszalek JR, Kitidis C, Dirusso CC, Lodish HF. Long-chain acyl-CoA synthetase 6 preferentially promotes DHA metabolism. J Biol Chem. 2005;280: 10817–10826. doi: 10.1074/jbc.M411750200 15655248
27. Van Horn CG, Caviglia JM, Li LO, Wang S, Granger DA, Coleman RA. Characterization of Recombinant Long-Chain Rat Acyl-CoA Synthetase Isoforms 3 and 6: Identification of a Novel Variant of Isoform 6. Biochemistry. 2005;44: 1635–1642. doi: 10.1021/bi047721l 15683247
28. Faergeman NJ, Knudsen J. Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J. 1997;323 Pt 1: 1–12. 9173866
29. Neess D, Bek S, Engelsby H, Gallego SF, Færgeman NJ. Long-chain acyl-CoA esters in metabolism and signaling: Role of acyl-CoA binding proteins. Prog Lipid Res. 2015;59: 1–25. doi: 10.1016/j.plipres.2015.04.001 25898985
30. Pasaje CFA, Bae JS, Park B-L, Jang A-S, Uh S-T, Kim M-K, et al. Association analysis of DTD1 gene variations with aspirin-intolerance in asthmatics. Int J Mol Med. 2011;28: 129–137. doi: 10.3892/ijmm.2011.669 21479357
31. Schroeder F, Atshaves BP, McIntosh AL, Gallegos AM, Storey SM, Parr RD, et al. Sterol carrier protein-2: new roles in regulating lipid rafts and signaling. Biochim Biophys Acta. 2007;1771: 700–718. doi: 10.1016/j.bbalip.2007.04.005 17543577
32. Seedorf U, Ellinghaus P, Roch Nofer J. Sterol carrier protein-2. Biochim Biophys Acta. 2000;1486: 45–54. 10856712
33. Edqvist J, Blomqvist K. Fusion and fission, the evolution of sterol carrier protein-2. J Mol Evol. 2006;62: 292–306. doi: 10.1007/s00239-005-0086-3 16501878
34. Schaeffer L, Gohlke H, Müller M, Heid IM, Palmer LJ, Kompauer I, et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet. 2006;15: 1745–1756. doi: 10.1093/hmg/ddl117 16670158
35. Malerba G, Schaeffer L, Xumerle L, Klopp N, Trabetti E, Biscuola M, et al. SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease. Lipids. 2008;43: 289–299. doi: 10.1007/s11745-008-3158-5 18320251
36. Rzehak P, Heinrich J, Klopp N, Schaeffer L, Hoff S, Wolfram G, et al. Evidence for an association between genetic variants of the fatty acid desaturase 1 fatty acid desaturase 2 (FADS1 FADS2) gene cluster and the fatty acid composition of erythrocyte membranes. Br J Nutr. 2009;101: 20–26. doi: 10.1017/S0007114508992564 18479586
37. Lattka E, Illig T, Heinrich J, Koletzko B. FADS gene cluster polymorphisms: important modulators of fatty acid levels and their impact on atopic diseases. J Nutrigenet Nutrigenomics. 2009;2: 119–128. doi: 10.1159/000235559 19776639
38. Bokor S, Dumont J, Spinneker A, Gonzalez-Gross M, Nova E, Widhalm K, et al. Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios. J Lipid Res. 2010;51: 2325–2333. doi: 10.1194/jlr.M006205 20427696
39. 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: 10.1371/journal.pgen.1000338 19148276
40. Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS Genet. 2011;7: e1002193. doi: 10.1371/journal.pgen.1002193 21829377
41. Wu JHY, Lemaitre RN, Manichaikul A, Guan W, Tanaka T, Foy M, et al. Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu. Circ Cardiovasc Genet. 2013;6: 171–183. doi: 10.1161/CIRCGENETICS.112.964619 23362303
42. Guan W, Steffen BT, Lemaitre RN, Wu JHY, Tanaka T, Manichaikul A, et al. Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. Circ Cardiovasc Genet. 2014;7: 321–331. doi: 10.1161/CIRCGENETICS.113.000208 24823311
43. Mozaffarian D, Kabagambe EK, Johnson CO, Lemaitre RN, Manichaikul A, Sun Q, et al. Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. Am J Clin Nutr. 2015;101: 398–406. doi: 10.3945/ajcn.114.094557 25646338
44. Tintle NL, Pottala JV, Lacey S, Ramachandran V, Westra J, Rogers a., et al. A genome-wide association study of saturated, mono- and polyunsaturated red blood cell fatty acids in the Framingham Heart Offspring Study. Prostaglandins, Leukot Essent Fat Acids. Elsevier; 2015;94: 65–72.
45. Park JY, Narayan SB, Bennett MJ. Molecular assay for detection of the common carnitine palmitoyltransferase 1A 1436(C>T) mutation. Clin Chem Lab Med. 2006;44: 1090–1091. doi: 10.1515/CCLM.2006.196 16958601
46. Rajakumar C, Ban MR, Cao H, Young TK, Bjerregaard P, Hegele RA. Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I. J Lipid Res. 2009;50: 1223–1228. doi: 10.1194/jlr.P900001-JLR200 19181627
47. Lemas DJ, Wiener HW, O’Brien DM, Hopkins S, Stanhope KL, Havel PJ, et al. Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup’ik Eskimos. J Lipid Res. 2012;53: 175–184. doi: 10.1194/jlr.P018952 22045927
48. Zhou S, Xiong L, Xie P, Ambalavanan A, Bourassa C V., Dionne-Laporte A, et al. Increased Missense Mutation Burden of Fatty Acid Metabolism Related Genes in Nunavik Inuit Population. Prokunina-Olsson L, editor. PLoS One. 2015;10: e0128255. doi: 10.1371/journal.pone.0128255 26010953
49. Clemente FJ, Cardona A, Inchley CE, Peter BM, Jacobs G, Pagani L, et al. A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. Am J Hum Genet. 2014;95: 584–589. doi: 10.1016/j.ajhg.2014.09.016 25449608
50. McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997;244: 1–14. 9063439
51. Swanson ST, Foster DW, McGarry JD, Brown NF. Roles of the N- and C-terminal domains of carnitine palmitoyltransferase I isoforms in malonyl-CoA sensitivity of the enzymes: insights from expression of chimaeric proteins and mutation of conserved histidine residues. Biochem J. 1998;335 Pt 3: 513–519. 9794789
52. Brown NF, Mullur RS, Subramanian I, Esser V, Bennett MJ, Saudubray JM, et al. Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J Lipid Res. 2001;42: 1134–1142. 11441142
53. Akkaoui M, Cohen I, Esnous C, Lenoir V, Sournac M, Girard J, et al. Modulation of the hepatic malonyl-CoA—carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids 1. Biochem J. 2009;420: 429–438. doi: 10.1042/BJ20081932 19302064
54. Voruganti VS, Higgins PB, Ebbesson SOE, Kennish J, Göring HHH, Haack K, et al. Variants in CPT1A, FADS1, and FADS2 are Associated with Higher Levels of Estimated Plasma and Erythrocyte Delta-5 Desaturases in Alaskan Eskimos. Front Genet. 2012;3: 86. doi: 10.3389/fgene.2012.00086 22701466
55. Buckley JD, Howe PRC. Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids. Obes Rev. 2009;10: 648–659. doi: 10.1111/j.1467-789X.2009.00584.x 19460115
56. Wang Y-X, Lee C-H, Tiep S, Yu RT, Ham J, Kang H, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell. 2003;113: 159–170. 12705865
57. Zurlo F, Lillioja S, Esposito-Del Puente A, Nyomba BL, Raz I, Saad MF, et al. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am J Physiol. 1990;259: E650–657. 2240203
58. Simoneau JA, Veerkamp JH, Turcotte LP, Kelley DE. Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J. 1999;13: 2051–2060. 10544188
59. Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes. 2001;50: 123–130. 11147777
60. Lemaitre RN, King IB, Kabagambe EK, Wu JHY, McKnight B, Manichaikul A, et al. Genetic loci associated with circulating levels of very long-chain saturated fatty acids. J Lipid Res. 2015;56: 176–184. doi: 10.1194/jlr.M052456 25378659
61. Hicks AA, Pramstaller PP, Johansson Å, Vitart V, Rudan I, Ugocsai P, et al. Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations. Gibson G, editor. PLoS Genet. 2009;5: e1000672. doi: 10.1371/journal.pgen.1000672 19798445
62. Demirkan A, van Duijn CM, Ugocsai P, Isaacs A, Pramstaller PP, Liebisch G, et al. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. PLoS Genet. 2012;8: e1002490. doi: 10.1371/journal.pgen.1002490 22359512
63. Bjerregaard P. Inuit Health in Transition Greenland survey 2005–2010 Population sample and survey methods [Internet]. 2011. Available: http://www.si-folkesundhed.dk/upload/inuit_health_in_transition_greenland_methods_5_2nd_revision.pdf
64. Bjerregaard P, Curtis T, Borch-Johnsen K, Mulvad G, Becker U, Andersen S, et al. Inuit health in Greenland: a population survey of life style and disease in Greenland and among Inuit living in Denmark. Int J Circumpolar Health. 2003;62 Suppl 1: 3–79. 14527126
65. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28: 412–419. 3899825
66. Bjerregaard P, Pedersen HS, Mulvad G. The associations of a marine diet with plasma lipids, blood glucose, blood pressure and obesity among the inuit in Greenland. Eur J Clin Nutr. 2000;54: 732–737. 11002386
67. Voight BF, Kang HM, Ding J, Palmer CD, Sidore C, Chines PS, et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. Medical Population Genetics, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.; 2012;8: e1002793. doi: 10.1371/journal.pgen.1002793;
68. Delaneau O, Zagury J-F. Data Production and Analysis in Population Genomics [Internet]. Pompanon F, Bonin A, editors. Methods in molecular biology (Clifton, N.J.). Totowa, NJ: Humana Press; 2012. doi: 10.1007/978-1-61779-870-2
69. Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5: e1000529. doi: 10.1371/journal.pgen.1000529 19543373
70. Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44: 821–824. doi: 10.1038/ng.2310 22706312
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2016 Číslo 6
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Endogenous Mouse Dicer Is an Exclusively Cytoplasmic Protein
- Public Service by a Selfish Gene: A Domesticated Transposase Antagonizes Polycomb Function
- Genetic Links between Recombination and Speciation
- Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders