Influence of the LDL-receptor genotype on statin response in heterozygous familial hypercholesterolemia: insights from the Canadian FH Registry.

Abstract Background Whether LDL receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL-C reductions in HeFH. Methods A total of 615 individuals with HeFH (receptor defective (RD) genotype, n=226; receptor negative (RN) genotype, n=389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared using linear models. Results There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with a RN genotype [Untreated: RN: 7.24 (95% CI: 6.98, 7.50) mmol/L vs. RD: 6.70 (95% CI: 6.41, 6.98) mmol/L; P=0.0002; on-statin: RN: 4.50 (95% CI: 4.31, 4.70) vs. RD: 4.05 (95% CI: 3.84, 4.26) mmol/L; P=0.0004)]. After adjustments for age, sex, smoking status, untreated LDL-C concentrations and statin type and dose as well as the clinic where the patients were treated, the LDL-C lowering effect of statins was significantly weaker for individuals with a RN mutation compared with individuals with a RD mutation [RN: -31.1% (95% CI: (-34.7, -27.4) vs. RD: -36.5% (95% CI: -40.4, -32.6); P 2 =2.3%; P=0.0001). Conclusion The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.