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

Abstract

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.

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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 (https://www.ebi.ac.uk/ega/home) with the accession EGAS00001002641.

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Acknowledgements

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.

Funding

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).

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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.

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Correspondence to Ninna Senftleber.

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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

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