Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Pharmacogenet Genomics. 2016 Jan;26(1):1-11. doi: 10.1097/FPC.0000000000000178.


Objectives: To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene.

Results: Men and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P<0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P<0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P<0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P<0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P<0.01 and P<0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response.

Conclusion: rs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women's response to statin therapy.

MeSH terms

  • Adult
  • Aged
  • Alternative Splicing*
  • Anticholesteremic Agents / pharmacology
  • Anticholesteremic Agents / therapeutic use
  • Canada
  • Cholesterol, LDL / blood*
  • Cholesterol, LDL / drug effects
  • Female
  • Genotype
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / genetics*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / drug therapy*
  • Hyperlipoproteinemia Type II / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Receptors, LDL / genetics
  • Sequence Deletion
  • Sex Factors


  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • LDLR protein, human
  • Receptors, LDL
  • HMGCR protein, human
  • Hydroxymethylglutaryl CoA Reductases