OBJECTIVE: Given the role of estrogen in the regulation of lipid metabolism, we screened for functional polymorphisms in the estrogen receptor alpha (ER*), and examined for their influence on serum cholesterol. METHODS AND RESULTS: We identified a novel C>T polymorphism (ERNE-145), with a minor allele frequency of 41%. This polymorphism was immediately adjacent to a putative glucocorticoid receptor (GR) binding site, which we showed to be functional by electrophoretic mobility shift analysis. The C allele was associated with glucocorticoid-induced reduction in promoter activity compared to control in luciferase reporter studies (p<0.05; n=7). This effect was abolished by the T allele. To investigate the functional significance of ERNE-145, its association with serum cholesterol levels was examined in 1662 post-menopausal women enrolled in the RUTH trial. ERNE-145 genotype (p=0.001), BMI (p<0.001), diabetes mellitus (p<0.001), and ethnicity (p=0.002) were significantly associated with HDL cholesterol. ERNE-145 genotype explained 8.2% of the variability of HDL: each copy of the variant T allele was associated with a 0.041 mmol/L (CI 0.017-0.066) increase in HDL. CONCLUSION: A novel polymorphism upstream of ER* abolished negative transcriptional regulation by an adjacent GR binding sequence, and was strongly associated with HDL levels in a large cohort of post-menopausal women.
OBJECTIVE: Given the role of estrogen in the regulation of lipid metabolism, we screened for functional polymorphisms in the estrogen receptor alpha (ER*), and examined for their influence on serum cholesterol. METHODS AND RESULTS: We identified a novel C>T polymorphism (ERNE-145), with a minor allele frequency of 41%. This polymorphism was immediately adjacent to a putative glucocorticoid receptor (GR) binding site, which we showed to be functional by electrophoretic mobility shift analysis. The C allele was associated with glucocorticoid-induced reduction in promoter activity compared to control in luciferase reporter studies (p<0.05; n=7). This effect was abolished by the T allele. To investigate the functional significance of ERNE-145, its association with serum cholesterol levels was examined in 1662 post-menopausal women enrolled in the RUTH trial. ERNE-145 genotype (p=0.001), BMI (p<0.001), diabetes mellitus (p<0.001), and ethnicity (p=0.002) were significantly associated with HDL cholesterol. ERNE-145 genotype explained 8.2% of the variability of HDL: each copy of the variant T allele was associated with a 0.041 mmol/L (CI 0.017-0.066) increase in HDL. CONCLUSION: A novel polymorphism upstream of ER* abolished negative transcriptional regulation by an adjacent GR binding sequence, and was strongly associated with HDL levels in a large cohort of post-menopausal women.
Authors: Hassan S Dashti; Jack L Follis; Caren E Smith; Toshiko Tanaka; Marta Garaulet; Daniel J Gottlieb; Adela Hruby; Paul F Jacques; Jessica C Kiefte-de Jong; Stefania Lamon-Fava; Frank A J L Scheer; Traci M Bartz; Leena Kovanen; Mary K Wojczynski; Alexis C Frazier-Wood; Tarunveer S Ahluwalia; Mia-Maria Perälä; Anna Jonsson; Taulant Muka; Ioanna P Kalafati; Vera Mikkilä; José M Ordovás Journal: Diabetes Care Date: 2015-06-17 Impact factor: 19.112