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A common missense variant of LILRB5 is associated with statin intolerance and myalgia.

Abstract

Aims

A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.

Methods and results

In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34-2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07-1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05-2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10-1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16-1.54).

Conclusion

This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

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  • Authors+Show Affiliations

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Institute of Translation Medicine, University of Liverpool, Liverpool L69 3BX, UK.

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    Institute of Translation Medicine, University of Liverpool, Liverpool L69 3BX, UK.

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    Department of Medical Sciences, Clinical Pharmacology and Science of Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.

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    Medical Products Agency, Dag Hammarskjölds väg 42, 75237 Uppsala, Sweden.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK. Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH4 2XU, UK.

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    Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Institute of Translation Medicine, University of Liverpool, Liverpool L69 3BX, UK.

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    Brigham and Women's Hospital, Department of Medicine, Preventive Medicine, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

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    Ninewells Hospital and Medical School, Dundee DD19SY, UK.

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    Institute of Translation Medicine, University of Liverpool, Liverpool L69 3BX, UK.

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    Department of Medical Sciences, Clinical Pharmacology and Science of Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.

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    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, The Netherlands. Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

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    Brigham and Women's Hospital, Department of Medicine, Preventive Medicine, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

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    Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD19SY, UK.

    Source

    European heart journal 38:48 2017 Dec 21 pg 3569-3575

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29020356