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

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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.
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Keywords: alternative splicing; familial hypercholesterolemia; genetic polymorphism; human 3-hydroxy-3-methylglutaryl-CoA reductase; rs3846662; serum lipid levels; statin efficacy

Document Type: Research Article

Affiliations: 1: Douglas Mental Health University Institute, McGill University, Department of Nutrition, Clinical Research Institute of Montreal (IRCM), Montreal University, Montreal, Quebec, Canada 2: Department of Nutrition, Clinical Research Institute of Montreal (IRCM), Montreal University, Montreal, Quebec, Canada 3: Centre for Studies in Alzheimer’s disease prevention, Douglas Mental Health University Institute, McGill University

Publication date: January 1, 2016

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