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

Abstract

Background and Aims The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentration of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance. Methods and Results A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance (general statin intolerance: ORGSI 2.42[95%CI:1.29, 4.31], p = 0.003; statin-related myopathy ORSRM 2.51[95%CI:1.28, 4.53], p = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85[95%CI:1.03, 6.65], p = 0.02). In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99 [95%CI:1.01, 3.95], p = 0.048; ORGRS 1.76 [95%CI:1.16, 2.69], p = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared to Val174Ala (general statin intolerance: HRVal174Ala 2.49 [95%CI:1.09, 5.68], p = 0.03; HRGRS 2.44 [95%CI:1.46, 4.08], p < 0.001). Finally, sequence kernel association testing (SKAT) confirmed rare variants in SLCO1B1 are associated with the risk of intolerance (p = 0.02). Conclusions We provide evidence that a gene risk score based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early onset statin intolerance.

SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients

“…In our study these variants improved the estimates for statin outcomes in UK Biobank patients when combined into a gene risk score (GRS); in "high risk" patients (i.e., carrying a *5 risk allele and no GoF alleles), GP-diagnosed muscle symptoms were higher (HR: 1.13, p = 0.02) than the estimate for *5 CC allele carriers alone (HR: 1.09, p = 0.048), compared to non-carriers. These findings partially replicate the Bigossi et al [19] GRS in 15,378 statin users, where incorporating GoF variants into the GRS improved the prediction of SAMS. The authors also included SLCO1B1*37 in the GRS, defining the G-allele as protective.…”

“…The authors also included SLCO1B1*37 in the GRS, defining the G-allele as protective. Other studies report that the G-allele protects against statin-related adverse events in 4196 [6] and 15,378 statin patients [19]. In our analysis, we found that the *37 G-allele increased the risk of statin adverse outcomes when included in the GRS.…”

“…We calculated the gene scores GRS-1 ("High risk" rs4149056 -*5 CC allele, or CT for *5 and rs2306283-AA (*20), rs11045819-CC (*4), or rs34671512-AA (*19), as reported by Bigossi et al [19]) and GRS-2 (using rs2306283-GG instead of the AA allele) (see methods for details).…”

“…Common SLCO1B1 "gain-of-function" (GoF) variants (rs11045819:Pro155Thr and rs34671512:Leu643Phe) increase simvastatin bioavailability [18], but their effects on the statin response remain unclear. A recent study in 15,378 statin users combined four common SLCO1B1 variants into a gene risk score; high-risk patients had increased odds of statin intolerance, and accounting for GoF variants improved prediction [19].…”

The impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy optimization in men and women with familial hypercholesterolemia

“…In this context, in our study the genetic evaluation of SLCO1B1 rs4149056 presence was able to detect FH subjects who reported myalgia, discontinued high intensity statins and did not achieve the recommended LDL-C target. Thus, the application of a genetic tool able to identify subjects at higher risk of statin intolerance could be useful to ameliorate LLT management in FH subjects more vulnerable to cardiovascular injury (37).…”