Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records

Abstract

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored.Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy.Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001).Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.

The cholesterol-lowering effect of statins is modified by LILRB5 intolerance genotype: Results from a recruit-by-genotype clinical trial

“…Further, the study participants were healthy and not suffering from cardiovascular diseases, which may influence the level of low-grade inflammation and modulate the immunological response to statin therapy as to attenuate genetic effects. While this might limit the generalizability of our findings, the age of the study subjects represents the typical age of patients prescribed statins ( Melhem et al, 2021 ). Statin ADRs, and statin-induced myopathy among them, are more common in aged individuals and senescent animal models ( Camerino et al, 2016 ; Arrigoni et al, 2017 ; Ward et al, 2019 ; Belch et al, 2021 ).…”

“…Our observed effect of LILRB5 genotype on non-HDL cholesterol response is supported by previous findings from the Tayside bioresource. In the study by Melhem et al non-HDL -cholesterol response was defined as lowest measured non-HDL cholesterol, after a minimum of 4 weeks of statin therapy up to a maximum of 6 months after commencement of statin therapy ( Melhem et al, 2021 ). Individuals with the C/C genotype had an absolute reduction of 0.05 mmol/L (0.01,0.08, p < 0.05) greater than carriers of the T/T genotype.…”

Ezetimibe ameliorates clinical symptoms in a mouse model of ankylosing spondylitis associated with suppression of Th17 differentiation

“…We confirmed the anti-inflammatory effect of ezetimibe in vivo in humans and mice, as well as in vitro . Statins typically have mild side effects but can cause severe muscle damage, inflammation of the liver and pancreas, and memory problems; they can also reduce the blood platelet count ( 59 ). Ezetimibe has fewer side effects than statins ( 60 , 61 ).…”

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

“…These bioresources have been previously used to make discoveries in the pharmacogenetics of statins, blood pressure medications, and anti-diabetic drugs. 26–30 …”