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.

• Authors: Moneeza K Siddiqui, Cyrielle Maroteau, Abirami Veluchamy, Aleksi Tornio, Roger Tavendale, Fiona Carr, Ngu-Uma Abelega, Dan Carr, Katyrzyna Bloch, Par Hallberg, 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 Alfirevic, Mia Wadelius, Anke-Hilse Maitland-van der Zee, Daniel I Chasman, Colin N A Palmer, PREDICTION-ADR Consortium
• Journal: European heart journal (Eur Heart J) Vol. 38 Issue 48 Pg. 3569-3575 (12 21 2017) ISSN: 1522-9645 [Electronic] England
• PMID: 29020356 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• Antigens, CD
• Biomarkers
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• LILRB5 protein, human
• Receptors, Immunologic
• Rosuvastatin Calcium
• DNA
• L-Lactate Dehydrogenase
• Creatine Kinase

Topics

• Antigens, CD (genetics, metabolism)
• Biomarkers (blood)
• Creatine Kinase (blood)
• DNA (genetics)
• DNA Mutational Analysis
• Drug Tolerance
• Dyslipidemias (blood, drug therapy)
• Female
• Genotype
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects, therapeutic use)
• L-Lactate Dehydrogenase (blood)
• Male
• Middle Aged
• Mutation, Missense
• Myalgia (chemically induced, diagnosis, genetics)
• Phenotype
• Receptors, Immunologic (genetics, metabolism)
• Rosuvastatin Calcium (adverse effects, therapeutic use)