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

Abstract

AimsA 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 resultsIn 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).ConclusionThis 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.

Clinical evidence of pharmacogenetics of statins: systematic literature review

“…Leusink et al (2014) [40] Case-control We found no association of the CYP3A4*22 minor allele (rs35599367) with the effectiveness of statins in reducing MI risk. Siddiqui et al (2017) [25] Meta-analysis Consistent association between Asp247Gly and outcomes associated with SI. Luzum et al (2015) [30] Case-control Our results do not replicate the association between GATM rs9806699 and SIM.…”

“…One meta-analysis and one case-control showed a true association of LILRB5 mutation (rs12975366: T>C: Asp247Gly). [25] Also, possible association of HLA-DRB1 carriers with SIM through an immune-mediated necrotising mechanism by the production of an autoantibody against HMGCR, a target molecule of statin, was determined, and the association of HLA-DRB1*11:01 with antibody-positive myopathy was shown in different populations. [17] RYR2 gene…”

“…The literature search was limited by available databases and access. The number of publications in this topic is relatively [9,[13][14][15] X X SLCO1B1 [16,17] X X APOE [9,10,14,18,19] X X PON1 [23,24] X X RYR2 [27] X X RYR2 [17] X X TLR4, [10] LTa C804A, [31] LPA, [9] NPC1L1, [18] HLA-G, [32] CYP3A4*2, [33] eNOS, [33] CYP2D6, [34] ABCB1, [35] CETP, [14] SREBF1,2, [36] KIF16, [37] HMGCR, [14,19] SORT1/CELSR2/PSRC1 [19,24] X X ACE, [10] HL, [10] WDR52, [38] CDH13, [39] CYP3A4*2 [40] X X HLA-DRB1, [17] LILRB5 [25] X X COQ2, [15] GATM [17,30] X X Pharmacogentics of statins Anas S. Aldawsari and Mohammad S. Shawaqfeh scares which made the literature search a real challenge. There were limited numbers of randomised controlled studies and meta-analysis in the topic.…”

Pharmacogenetics of Cardiovascular Disease: Genetic Variation and Statin Intolerance

“…A potential role for immune system genetic variation in development of statin-induced myopathy has been recently reported for a variant in leukocyte immunoglobulin-like receptor subfamily-B, LILRB5 gene (rs12975366:T > C:Asp247Gly) [25]. The missense variant Asp247Gly has been associated with serum creatine kinase (CK) levels; the mean levels of this enzyme were elevated in Asp247 homozygotes (TT).…”

“…The missense variant Asp247Gly has been associated with serum creatine kinase (CK) levels; the mean levels of this enzyme were elevated in Asp247 homozygotes (TT). The LILRB5 Asp247 homozygous genotype has, therefore, been associated with increased risk of statin intolerance [25]. No independent replication data on this plausible new variant has been available so far.…”