10/4/18 Disclosure Modifying Effect of ApoE4 Genotype on IS, HNH - PDF document

10/4/18 Disclosure Modifying Effect of ApoE4 Genotype on IS, HNH and WJM: Unrestricted research grant from • the Association Between Metabolic Phenotype Therapeutics MD and Subclinical Atherosclerosis in Postmenopausal Women RK: No financial relationships to disclose • Intira Sriprasert 1 , Howard N. Hodis 1,2 , Wendy J. Mack 1,2 , Roksana Karim 1,2 Funded by NIA (R01AG-024154 and R01AG-059690) 1 Department of Preventive Medicine, Kec k School of M edicine, University of Southern C alifornia 2 Atherosclerosis Re search Unit, K eck Sc hool of Medicine, U nivers ity of Southern California Contact information: sriprase@usc.edu 2 Lipoprotein Apolipoprotein E (ApoE) ApoE4 genotypes and heart disease ApoC ApoB ApoE ApoE4 genotype increased risk of coronary heart disease • • (CHD) and subclinical atherosclerosis measured by carotid Synthesized primarily in liver • artery intima media thickness (CIMT) . A key protein in lipoprotein metabolism • Odds ratio for CHD Mean difference of CIMT from E3/E3 by ApoEphenotypes by ApoEphenotypes ApoE ApoE gene (19q13.2) • 3 ApoE allele frequencies • E2 0.02-0.08, E3 0.66-0.86, E4 0.1-0.3 • 6 ApoE genotypes • Homozygous: E2/E2, E3/E3, E4/E4 • Heterozygous: E2/E3, E2/E4, E3/E4 • Davignon J, et. al. Arteriosclerosis. 1988;8(1):1-21. Eichner JE, et. al. Am J Epidemiol. 2002;155(6):48 7-9 5. Aizawa Y , et. Al. Gastroenterol. 2015;21(36):1029 9-3 13. Bennet AM, et. al. JAMA. 2007;298(11):1300 -11. Khan TA, et. al. Int J Epidemiol. 2013;42(2):475-9 2. 3 4 Metabolic phenotype Objective A cluster of multiple risk factors for cardiovascular disease T o examine the modifying effect of ApoE4 genotype on • • the association between metabolic phenotypes and subclinical atherosclerosis among early and late Metabolic syndrome • Meta-analysis of mean CIMT difference postmenopausal women using data from the Early High blood pressure • by metabolic syndrome versus Late Intervention Trial with Estradiol (ELITE). Hyperglycemia • Elevated triglyceride • Low high-density lipoprotein cholesterol • Abdominal obesity • Metabolic syndrome is associated • MS lower MS higher with CIMT (p<0.0001) Cuspidi C, et. al. J Hypertens. 2018;36(1):23-30. 5 6 1

10/4/18 ELITE Material and Methods Double blinded, placebo-controlled randomized clinical trial Study design and study population • • Tested whether the effect of hormone therapy (HT) on Cross-sectional and longitudinal analysis of trial data • • atherosclerosis progression differed by time since menopause Postmenopausal women from the ELITE trial with available ApoE • Healthy postmenopausal women without CHD, diabetes genotype were included in the analysis (497 of 643) • Oral micronized 17-beta-estradiol 1 mg/day • 4% vaginal micronized progesterone gel 45 mg/day (10 days/month) Subclinical atherosclerosis • Results • Common carotid artery intima media thickness (CIMT) measured • Among early postmenopausal (< 6 years-since-menopause) women • with B-mode ultrasound at baseline and every 6 months for 4.8 years HT significantly reduced CIMT progression Among late postmenopausal (≥ 10 years-since-menopause) women • ApoE4 genotype • HT had no effect on CIMT progression ApoE4 positive (E2/E4, E3/E4, E4/E4) • ApoE4 negative (E2/E2, E3/E3, E2/E3) • Hodis HN, et al. Menopause. 2015;22(4):391-4 01. 7 8 Material and Methods Statistical Analysis Metabolic phenotypes ANOVA and Chi-square test • • A principal component analysis and K-means clustering analysis Compared baseline characteristics between ApoE4 genotype by • metabolic phenotype were used with baseline levels of 9 metabolic biomarkers. General linear models • Tested whether the cross-sectional association between metabolic • phenotype and baseline CIMT differs by ApoE4 genotype after adjusting for age Linear mixed effects models • Evaluated whether the longitudinal association between metabolic • phenotype and CIMT progression differs by ApoE4 genotype over a median follow-up of 4.8 years Mean values of each variable Rettberg JR, et al. Neurobiol Aging. 2016;40:155-63. 9 10 Baseline characterist ics Baseline characterist ics by metabolic phenotype by metabolic phenotype and ApoE4 genotype *Bolded numbers indicate significan t difference among phe notyp es (p<0.05). *Bolded numbers indicate significan t difference between ApoE4 geno type (p<0.05) **Red numbers indica te the highest values across gro ups 11 12 2

10/4/18 Cross-sectional analysis Cross-sectional analysis Mean CIMT (SE) at baseline Mean CIMT (SE) at baseline by metabolic phenotype and ApoE4 genotype by metabolic phenotype and ApoE4 genotype Early postmenopausal women Late postmenopausal women Total sample < 6 years-since-menopause ≥10 years-since-menopause ApoE4+ women with poor • metabolic phenotype had the highest CIMT. ApoE4 genotype significantly • modified the effect of metabolic phenotype on CIMT. ApoE4*metabolic phenotype interaction p = 0.001 ApoE4*metabolic phenotype ApoE4*metabolic phenotype interaction p = 0.05 interaction p = 0.02 13 14 Longitudinal analysis Discussion Mean CIMT (SE) progression by metabolic phenotype and ApoE4 genotype The adverse impact of metabolic dysregulation on CIMT • is modified by ApoE4 genotype. Total sample ApoE4+ women with high blood • The impact was apparent only in women with ApoE4 positive • pressure phenotype and poor genotype. metabolic phenotype had the highest CIMT progression rate. This modifying effect was found only in cross-sectional • but not longitudinal analysis. ApoE4 genotype did not modify • Baseline effect reflects long-term exposure effects and the effect of metabolic • cumulative progression of atherosclerosis. phenotype on CIMT. Inability to detect the longitudinal effect due to small sample size ApoE4*metabolic phenotype*time • interaction p = 0.79 and limited follow-up time. 15 16 Discussion Conclusion ApoE4 is also the major genetic risk factor for ApoE4 positive women with poor metabolic phenotype • • Alzheimer’s disease. have higher levels of subclinical atherosclerosis. We have similarly shown the adverse impact of Identification of high risk women • • metabolic dysregulation on cognition, specifically among ApoE4 positive • ApoE4 positive women. Elevated LDL, triglyceride, glucose, HbA1C, HOMA score • ApoE4*metabolic phenotype interaction p = 0.003 Lowered HDL • • Preventive intervention strategies targeting high risk • women to reduce the burden of coronary heart disease. Karim R, et al. Menopause. 2018. 17 18 3