Genetic study of the Arctic CPT1A variant suggests that its effect on fatty acid levels is modulated by traditional Inuit diet


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Plots of the significant (p < 0.00417, C and F) and nominal significant (p < 0.05, A, B, D, and E) interaction effects from standard interaction model adjusted for age, sex, cell type measured (erythrocytes or all blood cells), SNP effect, and diet as fixed effects and including the genetic similarity matrix as random effect.
Fig. 2: QQ plots of the genome-wide association study of the CPT1A × traditional diet interaction.

Data availability

The Greenlandic Metabochip-genotype data are deposited in the European Genome-phenome Archive ( with the accession EGAS00001002641.


  1. 1.

    Pars T, Osler M, Bjerregaard P. Contemporary use of traditional and imported food among Greenlandic Inuit. Arctic. 2001;54:22–31.

    Article  Google Scholar 

  2. 2.

    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.

    Article  Google Scholar 

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    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.

    Article  Google Scholar 

  5. 5.

    McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system—from concept to molecular analysis. Eur J Biochem. 1997;244:1–14.

    CAS  Article  Google Scholar 

  6. 6.

    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.

    CAS  PubMed  Google Scholar 

  7. 7.

    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.

    Google Scholar 

  8. 8.

    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.

    CAS  Article  Google Scholar 

  9. 9.

    Sowa F. Kalaalimernit: the Greenlandic taste for local foods in a globalised world. Polar Rec. 2015;51:290–300.

    Article  Google Scholar 

  10. 10.

    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.

    Article  Google Scholar 

  11. 11.

    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.

    Article  Google Scholar 

  12. 12.

    Jeppesen C, Bjerregaard P. Consumption of traditional food and adherence to nutrition recommendations in Greenland. Scand J Public Health. 2012;40:475–81.

    Article  Google Scholar 

  13. 13.

    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.

    CAS  Article  Google Scholar 

  14. 14.

    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.

    Article  Google Scholar 

  15. 15.

    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.

    CAS  Article  Google Scholar 

  16. 16.

    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.

    CAS  Article  Google Scholar 

  17. 17.

    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.

  18. 18.

    Willett W. Issues in analysis and presentation of dietary data: nutritional epidemiology. 3rd ed. Oxford: Oxford University Press; 2013. p. 305–32.

  19. 19.

    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.

    CAS  Article  Google Scholar 

  20. 20.

    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.

    Article  Google Scholar 

  21. 21.

    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.

    Article  Google Scholar 

  22. 22.

    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.

    Article  Google Scholar 

  23. 23.

    Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr. 1997;65:1220–8.

    Article  Google Scholar 

  24. 24.

    Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44:821–4.

    CAS  Article  Google Scholar 

  25. 25.

    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.

    Article  Google Scholar 

  26. 26.

    Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004.

    CAS  Article  Google Scholar 

  27. 27.

    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.

    Article  Google Scholar 

  28. 28.

    Di Pasquale MG. The essentials of essential fatty acids. J Diet. 2009;6:143–61.

    Article  Google Scholar 

  29. 29.

    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.

  30. 30.

    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.

    CAS  PubMed  Google Scholar 

  31. 31.

    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.

    CAS  Article  Google Scholar 

  32. 32.

    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.

    Article  Google Scholar 

  33. 33.

    Andersen MK, Hansen T. Genetics of metabolic traits in Greenlanders: lessons from an isolated population. J Intern Med. 2018;284:464–77.

    CAS  Article  Google Scholar 

  34. 34.

    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.

    CAS  Article  Google Scholar 

  35. 35.

    ICF Consulting Services Ltd. Consumption and impact of high fructose syrups. Luxemborg: European Union; 2018.

    Google Scholar 

  36. 36.

    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.

    Article  Google Scholar 

Download references


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).

Author information




NKS and AA designed the project with input from MEJ, FI, and NGF; NKS undertook the statistical analyses with help from EJ; NKS wrote the majority of the manuscript with critical input from AA, FI, and MEJ. NKS, MEJ, EJ, FI, NGF, CLL, PB, TH, and AA read, commented, and approved the manuscript.

Corresponding author

Correspondence to Ninna Senftleber.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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).

Download citation

Further reading