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Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-Wide Association Studies from the CHARGE Consortium

Author

Listed:
  • Rozenn N Lemaitre
  • Toshiko Tanaka
  • Weihong Tang
  • Ani Manichaikul
  • Millennia Foy
  • Edmond K Kabagambe
  • Jennifer A Nettleton
  • Irena B King
  • Lu-Chen Weng
  • Sayanti Bhattacharya
  • Stefania Bandinelli
  • Joshua C Bis
  • Stephen S Rich
  • David R Jacobs Jr.
  • Antonio Cherubini
  • Barbara McKnight
  • Shuang Liang
  • Xiangjun Gu
  • Kenneth Rice
  • Cathy C Laurie
  • Thomas Lumley
  • Brian L Browning
  • Bruce M Psaty
  • Yii-Der I Chen
  • Yechiel Friedlander
  • Luc Djousse
  • Jason H Y Wu
  • David S Siscovick
  • André G Uitterlinden
  • Donna K Arnett
  • Luigi Ferrucci
  • Myriam Fornage
  • Michael Y Tsai
  • Dariush Mozaffarian
  • Lyn M Steffen

Abstract

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10−64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10−58) and docosapentaenoic acid (DPA, p = 4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10−12) and DPA (p = 1×10−43) and lower docosahexaenoic acid (DHA, p = 1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries. Author Summary: Circulating long-chain n-3 polyunsaturated fatty acids (PUFAs) derive from fatty fish or from the conversion of the plant n-3 PUFA by elongation and desaturation. We looked for common genetic markers throughout the genome that might influence plasma phospholipid levels of the four major n-3 PUFAs in five large studies and pooled the results. We found that levels of all four n-3 PUFAs were associated with genetic markers in known desaturation and elongation genes. We also found evidence that conversion of the plant n-3 PUFA to longer chain n-3 PUFAs is less effective in people with certain desaturation-gene markers, which could be important for people who do not eat fish. We also found a marker in a gene involved in glucose metabolism, called the glucokinase regulator, to be associated with one intermediate n-3 PUFA. Some of these findings were seen across multiple race/ethnicities. Overall, these results have implications for how genes and the environment interact to influence circulating levels of fatty acids.

Suggested Citation

  • Rozenn N Lemaitre & Toshiko Tanaka & Weihong Tang & Ani Manichaikul & Millennia Foy & Edmond K Kabagambe & Jennifer A Nettleton & Irena B King & Lu-Chen Weng & Sayanti Bhattacharya & Stefania Bandinel, 2011. "Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-Wide Association Studies from the CHARGE Consortium," PLOS Genetics, Public Library of Science, vol. 7(7), pages 1-12, July.
  • Handle: RePEc:plo:pgen00:1002193
    DOI: 10.1371/journal.pgen.1002193
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    Cited by:

    1. Andrea Ganna & Samira Salihovic & Johan Sundström & Corey D Broeckling & Åsa K Hedman & Patrik K E Magnusson & Nancy L Pedersen & Anders Larsson & Agneta Siegbahn & Mihkel Zilmer & Jessica Prenni & Jo, 2014. "Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease," PLOS Genetics, Public Library of Science, vol. 10(12), pages 1-10, December.
    2. Usman A. Tahir & Daniel H. Katz & Julian Avila-Pachecho & Alexander G. Bick & Akhil Pampana & Jeremy M. Robbins & Zhi Yu & Zsu-Zsu Chen & Mark D. Benson & Daniel E. Cruz & Debby Ngo & Shuliang Deng & , 2022. "Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Zhening Liu & Hangkai Huang & Jiarong Xie & Yingying Xu & Chengfu Xu, 2024. "Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Dariush Mozaffarian & Hassan S Dashti & Mary K Wojczynski & Audrey Y Chu & Jennifer A Nettleton & Satu Männistö & Kati Kristiansson & Mägi Reedik & Jari Lahti & Denise K Houston & Marilyn C Cornelis &, 2017. "Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts," PLOS ONE, Public Library of Science, vol. 12(12), pages 1-15, December.
    5. Tsion Zewdu Minas & Brittany D. Lord & Amy L. Zhang & Julián Candia & Tiffany H. Dorsey & Francine S. Baker & Wei Tang & Maeve Bailey-Whyte & Cheryl J. Smith & Obadi M. Obadi & Anuoluwapo Ajao & Symon, 2023. "Circulating trans fatty acids are associated with prostate cancer in Ghanaian and American men," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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