Several recent studies have found signs of recent selection on the carnitine palmitoyl-transferase 1A (CPT1A) gene in the ancestors of Arctic populations likely as a result of their traditional diet. CPT1A is involved in fatty acid transportation and is known to affect circulating fatty acid profiles in Inuit as does the unique traditional diet rich in marine animals. We aimed to assess which fatty acids may have driven the selection of rs80356779, a c.1436C>T (p.(Pro479Leu)) variant in CPT1A, by analyzing a potential interaction between the variant and traditional Inuit diet. We included 3005 genome-wide genotyped individuals living in Greenland, who had blood cell membrane fatty acid levels measured. Consumption of 25 traditional food items was expressed as percentage of total energy intake. We tested for CPT1A × traditional diet interaction while taking relatedness and admixture into account. Increasing intakes of traditional diet was estimated to attenuate the effect of 479L on 20:3 omega-6 levels (p = 0.000399), but increase the effect of the variant on 22:5 omega-3 levels (p = 0.000963). The 479L effect on 22:5 omega-3 more than doubled in individuals with a high intake of traditional diet (90% percentile) compared with individuals with a low intake (10% percentile). Similar results were found when assessing interactions with marine foods. Our results suggest that the association between traditional diet and blood cell fatty acid composition is affected by the CPT1A genotype, or other variants in linkage disequilibrium, and support the hypothesis that omega-3 fatty acids may have been important for adaptation to the Arctic diet.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The Greenlandic Metabochip-genotype data are deposited in the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home) with the accession EGAS00001002641.
Pars T, Osler M, Bjerregaard P. Contemporary use of traditional and imported food among Greenlandic Inuit. Arctic. 2001;54:22–31.
Raghavan M, DeGiorgio M, Albrechtsen A, Moltke I, Skoglund P, Korneliussen TS, et al. The genetic prehistory of the New World Arctic. Science. 2014;345:1255832.
Fumagalli M, Moltke I, Grarup N, Racimo F, Bjerregaard P, Jørgensen ME, et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science. 2015;349:1343–7.
Skotte L, Koch A, Yakimov V, Zhou SR, Søborg B, Andersson M, et al. CPT1A missense mutation associated with fatty acid metabolism and reduced height in Greenlanders. Circ-Cardiovasc Genet. 2017;10:1–9.
McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system—from concept to molecular analysis. Eur J Biochem. 1997;244:1–14.
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;42:1134–42.
Andersen MK, Jørsboe E, Sandholt CH, Grarup N, Jørgensen ME, Færgeman NJ, et al. Identification of novel genetic determinants of erythrocyte membrane fatty acid composition among Greenlanders. PLoS Genet. 2016;12:1–19.
Rajakumar C, Ban MR, Cao HN, 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;50:1223–8.
Sowa F. Kalaalimernit: the Greenlandic taste for local foods in a globalised world. Polar Rec. 2015;51:290–300.
Linder M, Belhaj N, Sautot P, Arab Tehrany E. From Krill to Whale: an overview of marine fatty acids and lipid compositions. OCL. 2010;17:194–204.
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;71:1–8.
Jeppesen C, Bjerregaard P. Consumption of traditional food and adherence to nutrition recommendations in Greenland. Scand J Public Health. 2012;40:475–81.
Takkunen MJ, de Mello VD, Schwab US, Kuusisto J, Vaittinen M, Agren JJ, et al. Gene-diet interaction of a common FADS1 variant with marine polyunsaturated fatty acids for fatty acid composition in plasma and erythrocytes among men. Mol Nutr Food Res. 2016;60:381–9.
Juan J, Huang HY, Jiang X, Korat AVA, Song MY, Sun Q, et al. Joint effects of fatty acid desaturase 1 polymorphisms and dietary polyunsaturated fatty acid intake on circulating fatty acid proportions. Am J Clin Nutr. 2018;107:826–33.
Smith CE, Follis JL, Nettleton JA, Foy M, Wu JHY, Ma YY, et al. Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium. Mol Nutr Food Res. 2015;59:1373–83.
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;95:584–9.
Bjerregaard P. Inuit health in transition—Greenland survey 2005–10. Population sample and survey methods. SIF writings on Greenland, vol 19. 2nd ed. Copenhagen: National Institute of Public Health; 2011.
Willett W. Issues in analysis and presentation of dietary data: nutritional epidemiology. 3rd ed. Oxford: Oxford University Press; 2013. p. 305–32.
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. 2015;96:54–69.
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. 2012;8:1–12.
Rudkowska I, Ouellette C, Dewailly E, Hegele RA, Boiteau V, Dube-Linteau A, et al. Omega-3 fatty acids, polymorphisms and lipid related cardiovascular disease risk factors in the Inuit population. Nutr Metab. 2013;10:1–9.
Da Silva MS, Julien P, Perusse L, Vohl MC, Rudkowska I. Natural rumen-derived trans fatty acids are associated with metabolic markers of cardiac health. Lipids. 2015;50:873–82.
Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr. 1997;65:1220–8.
Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44:821–4.
Keller MC. Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (Simple) solution. Biol Psychiatry. 2014;75:18–24.
Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004.
Del Gobbo LC, Imamura F, Aslibekyan S, Marklund M, Virtanen JK, Wennberg M, et al. Omega-3 polyunsaturated fatty acid biomarkers and coronary heart disease pooling project of 19 cohort studies. JAMA Intern Med. 2016;176:1155–66.
Di Pasquale MG. The essentials of essential fatty acids. J Diet. 2009;6:143–61.
Hooper L, Abdelhamid A, Ajabnoor S, Brainard J, Brown T, Hanson S, et al. Set of systematic reviews of RCTs on the health effects of omega 3 polyunsaturated fats in adults. World Health Organization; 2017.
Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos (Reprinted from Lancet, vol 2, pg 433, 1979). Nutrition. 1995;11:475.
Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder PC. Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations: analysis of 8 clinical studies with selected patient groups on omega-3-enriched medical nutrition. Clin Nutr. 2018;37:948–57.
Sinclair GB, Collins S, Popescu O, McFadden D, Arbour L, Vallance HD. Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations. Pediatrics. 2012;130:e1162–9.
Andersen MK, Hansen T. Genetics of metabolic traits in Greenlanders: lessons from an isolated population. J Intern Med. 2018;284:464–77.
Simopoulos AP. Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients. 2013;5:2901–23.
ICF Consulting Services Ltd. Consumption and impact of high fructose syrups. Luxemborg: European Union; 2018.
Lemaitre RN, Tanaka T, Tang WH, 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;7:1–12.
We would like to direct our acknowledgement to the staff and participants of the Inuit Health in Transition cohort facilitating this study as well as the Popgen group at the Bioinformatics Centre for a very helpful manuscript discussion.
NKS and AA are funded by the Lundbeck foundation (R215–2015–4174). NGF and FI acknowledge funding from the Medical Research Council Epidemiology Unit MC_UU_12015/5. NGF also acknowledges NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215–20014).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Senftleber, N., Jørgensen, M.E., Jørsboe, E. et al. Genetic study of the Arctic CPT1A variant suggests that its effect on fatty acid levels is modulated by traditional Inuit diet. Eur J Hum Genet 28, 1592–1601 (2020). https://doi.org/10.1038/s41431-020-0674-0