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

Moneeza K. Siddiqui, Cyrielle Maroteau, Abirami Veluchamy, Aleksi Tornio, Roger Tavendale, Fiona Carr, Ngu-Uma Abelega, Dan Carr, Katyrzyna Bloch, Par Halberg, Qun-Ying Yue, Ewan R. Pearson, Helen M. Colhoun, Andrew D. Morris, Eleanor Dow, Jacob George, Munir Pirmohamed, Paul M. Ridker, Alex S. F. Doney, Ana AlfirevicMia Wadelius, Anke Hilse Maitland-van der Zee, Daniel I. Chasman, Colin N. A. Palmer, PREDICTION-ADR Consortium

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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 & 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 (OR1.81;95%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.
Original languageEnglish
Pages (from-to)3569-3575
Number of pages7
JournalEuropean Heart Journal
Volume38
Issue number48
Early online date29 Aug 2017
DOIs
Publication statusPublished - 21 Dec 2017

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Keywords

  • Statins
  • Pharmacogenetics
  • Immunogenetics
  • Precision medicine
  • Adverse Drug Reactions
  • Myalgia

Cite this

Siddiqui, M. K., Maroteau, C., Veluchamy, A., Tornio, A., Tavendale, R., Carr, F., Abelega, N-U., Carr, D., Bloch, K., Halberg, P., Yue, Q-Y., Pearson, E. R., Colhoun, H. M., Morris, A. D., Dow, E., George, J., Pirmohamed, M., Ridker, P. M., Doney, A. S. F., ... PREDICTION-ADR Consortium (2017). A common missense variant of LILRB5 is associated with statin intolerance and myalgia. European Heart Journal, 38(48), 3569-3575. https://doi.org/10.1093/eurheartj/ehx467