The therapeutic effect of statins may be modified by genetic variation in PCSK9

Feng Q, Wie WQ, Chung CP, et al.
The Pharmacogenomics Journal 2016; published online ahead of print

Background

Increased LDL-C is an established risk factor for CVD, and LDL-C-lowering statins contribute to reduction of CVD by up to 50% in some populations [1-3]. However, a wide individual variation in LDL-C response to statins has been observed [4,5], raising interest in defining the genetic determinants of statin response.
Based on the current knowledge about LDL receptors (LDLR) and their regulation by statins and PCSK9 [6-9], it is hypothesised that subjects with PCSK9 variants of reduced function (PCSK9 loss-of-function or LOF) have an increased response to statins because the LDLR degradation would be reduced. However, data exploring the relationship between PCSK9 variants and the LDL-C response to statins led to conflicting results:

• in one study, out of 25 subjects who responded very well to statin therapy, only 3 had PCSK9 LOF variants [10]
• another study showed that response to statin therapy was not related to candidate PCSK9 variants [11]
• a study of 6,989 individuals of European ancestry, showed that a PCSK9 LOF variant (rs11591147, R46L) was associated to a greater response to rosuvastatin with locus-wide significance [12]

This study attempted to clarify whether 11 previously reported functional variants at the PCSK9 locus affect the magnitude of the LDL-C response to statin therapy, an important question since PCSK9 inhibitors are approved for use in combination with statins. The study cohort consisted of 669 self-identified African American and 2388 European American patients.

Main results

• Two previously described functional gain of function variants and 11 LOF variants in PCSK9 were identified in this cohort.

The LOF variant rs11591147 (R46L):

• the minor allele (T allele) was associated with a 55.6% greater LDL-C reduction in response to statins (P = 0.0024)
• remained significantly associated with LDL-C response to statin treatment in the nonparametric test (Wilcoxon rank-sum test, unadjusted P=0.096, after adjustment P = 0.026)
• was the most significant predictor for off-treatment (baseline) LDL-C levels (P=2.2×10^{− 4}):

- LDL-C of carriers: 72.33 ± 41.9 mg dl^{− 1} (n=3)
- LDL-C of non-carriers: 139.4 ± 44.8 mg dl^{− 1}

• was present in the European Ancestry cohort with a minor allele frequency (MAF) of 3.4%:

- it was strongly associated with off-treatment LDL-C levels (P = 2.7 × 10^-7)
- it was associated with an additional 7.0% reduction of LDL-C after statin treatment compared with non-carriers (P = 0.054)

• Another LOF variant, rs28362261 (N425S), was also associated with statin response (P = 0.0064) and a tendency for an association was seen with off-treatment LDL-C levels (P = 0.067).

Conclusion

Carriers of the LOF variant rs11591147 (R46L) in PCSK9 demonstrated significantly stronger statin response and had significantly lower off-treatment LDL-C levels, compared with non-carriers. This observation was documented in both African American and European American individuals, albeit with a smaller effect size in carriers of European ancestry. The results of this study support the hypothesis according to which the therapeutic effect of statins may be modified by genetic variation in PCSK9.

Find this article online at The Pharmacogenomics Journal

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