Valerie Leduc1, Lucienne Bourque, Judes Poirier, Robert Dufour. 1. aCentre for Studies in Alzheimer's disease prevention bDouglas Mental Health University Institute, McGill University cDepartment of Nutrition, Clinical Research Institute of Montreal (IRCM), Montreal University, Montreal, Quebec, Canada.
Abstract
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.
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.
Authors: C L Shear; F A Franklin; S Stinnett; D P Hurley; R H Bradford; A N Chremos; D T Nash; A Langendorfer Journal: Circulation Date: 1992-04 Impact factor: 29.690
Authors: Daniel I Chasman; David Posada; Lakshman Subrahmanyan; Nancy R Cook; Vincent P Stanton; Paul M Ridker Journal: JAMA Date: 2004-06-16 Impact factor: 56.272
Authors: Joel A Simon; Feng Lin; Stephen B Hulley; Patricia J Blanche; David Waters; Stephen Shiboski; Jerome I Rotter; Deborah A Nickerson; Huiying Yang; Mohammed Saad; Ronald M Krauss Journal: Am J Cardiol Date: 2006-01-27 Impact factor: 2.778
Authors: Sage M Wright; Samantha L Jensen; Kristen L Cockriel; Brian Davis; JoAnn T Tschanz; Ronald G Munger; Christopher D Corcoran; John S K Kauwe Journal: Neurobiol Aging Date: 2019-03-15 Impact factor: 4.673
Authors: Najmeh Ahangari; Mohammad Doosti; Majid Ghayour Mobarhan; Amirhossein Sahebkar; Gordon A Ferns; Alireza Pasdar Journal: Ann Med Date: 2020-08-24 Impact factor: 4.709