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Common variants associated with changes in levels of circulating free fatty acids after administration of glucose–insulin–potassium (GIK) therapy in the IMMEDIATE trial

The Pharmacogenomics Journal volume 17, pages 76–83 (2017)Cite this article

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Abstract

Glucose–insulin–potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10−7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10−7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10−7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.

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Acknowledgements

We would like to acknowledge William S Harris, Department of Internal Medicine, Sanford School of Medicine, University of South Dakota and OmegaQuant Analytics, Sioux Falls, SD, USA for his input and expertise regarding the interpretation of the results reported in this study. We would also like to offer our appreciation to all IMMEDIATE Genetic Ancillary Study participants. The Genetic Ancillary Study was funded by the National Institutes of Health (NIH) grant from National Heart, Lung and Blood Institute (NHLBI; R01HL090997). This work was also supported by National Center for Research Resources Grant Number UL1RR025752, now the National Center for Advancing Translational Sciences, NIH Grant Number Ul1 TR000073. The IMMEDIATE Trial was funded by the NIH cooperative agreement from NHLBI (U01HL077821, U01HL077823, and U01HL077826).

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    K L Ellis, E Ainehsazan & I Peter

  2. School of Medicine and Pharmacology and Centre for Genetic Origins of Health and Disease (GOHaD), Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, WA, Australia

    K L Ellis

  3. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Y Zhou & L A Cupples

  4. Departments of Pediatrics and Genetics and Genomic Sciences, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    L Rodriguez-Murillo

  5. Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA

    J R Beshansky & H P Selker

  6. Regulatory and Clinical Research Management, Regis College, Weston, MA, USA

    J R Beshansky

  7. Molecular Cardiology Research Institute Center for Translational Genomics, Tufts Medical Center, Boston, MA, USA

    G S Huggins

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Ellis, K., Zhou, Y., Rodriguez-Murillo, L. et al. Common variants associated with changes in levels of circulating free fatty acids after administration of glucose–insulin–potassium (GIK) therapy in the IMMEDIATE trial. Pharmacogenomics J 17, 76–83 (2017). https://doi.org/10.1038/tpj.2015.84

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