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Randomized Controlled Trial
. 2017 Dec 21;38(48):3569-3575.
doi: 10.1093/eurheartj/ehx467.

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

Moneeza K Siddiqui  1 , Cyrielle Maroteau  1 , Abirami Veluchamy  1 , Aleksi Tornio  1 , Roger Tavendale  1 , Fiona Carr  1 , Ngu-Uma Abelega  1 , Dan Carr  2 , Katyrzyna Bloch  2 , Par Hallberg  3 , Qun-Ying Yue  4 , Ewan R Pearson  1 , Helen M Colhoun  1   5 , Andrew D Morris  1   6 , Eleanor Dow  7 , Jacob George  7 , Munir Pirmohamed  2 , Paul M Ridker  8 , Alex S F Doney  7 , Ana Alfirevic  2 , Mia Wadelius  3 , Anke-Hilse Maitland-van der Zee  9   10 , Daniel I Chasman  8 , Colin N A Palmer  1 ; PREDICTION-ADR Consortium
Affiliations
Randomized Controlled Trial

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

Moneeza K Siddiqui et al. Eur Heart J. .

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.

Keywords: Adverse drug reactions; Immunogenetics; Myalgia; Pharmacogenetics; Precision medicine; Statins.

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Figures

Figure 1
Figure 1
Forest plot representing meta-analysis of the association between LILRB5 Asp247Gly and outcomes observed across GoDARTS, CPRD-STAGE, PREDICTION-ADR, and JUPITER studies. Study sample size is in parentheses. LDI, low-dose intolerance; SIM, statin-induced myopathy.
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