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

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Modifying Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women

Intira Sriprasert1, Howard N. Hodis1,2, Wendy J. Mack1,2 , Roksana Karim1,2 Funded by NIA (R01AG-024154 and R01AG-059690)

1Department of Preventive Medicine, Kec

k School of M edicine, University of Southern C alifornia

2Atherosclerosis Re

search Unit, K eck Sc hool of Medicine, U nivers ity of Southern California

Contact information: sriprase@usc.edu

• IS, HNH and WJM: Unrestricted research grant from

Therapeutics MD

• RK: No financial relationships to disclose

Disclosure

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• ApoE
• Synthesized primarily in liver
• A key protein in lipoprotein metabolism
• 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

Apolipoprotein E (ApoE)

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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.

Lipoprotein ApoE ApoC ApoB

• ApoE4 genotype increased risk of coronary heart disease

(CHD) and subclinical atherosclerosis measured by carotid artery intima media thickness (CIMT) .

ApoE4 genotypes and heart disease

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Bennet AM, et. al. JAMA. 2007;298(11):1300 -11. Khan TA, et. al. Int J Epidemiol. 2013;42(2):475-9 2.

Odds ratio for CHD by ApoEphenotypes Mean difference of CIMT from E3/E3 by ApoEphenotypes

• A cluster of multiple risk factors for cardiovascular disease
• Metabolic syndrome
• High blood pressure
• Hyperglycemia
• Elevated triglyceride
• Low high-density lipoprotein cholesterol
• Abdominal obesity
• Metabolic syndrome is associated

with CIMT (p<0.0001)

Metabolic phenotype

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Cuspidi C, et. al. J Hypertens. 2018;36(1):23-30.

Meta-analysis of mean CIMT difference by metabolic syndrome

MS lower MS higher

• T
• examine the modifying effect of ApoE4 genotype on

the association between metabolic phenotypes and subclinical atherosclerosis among early and late postmenopausal women using data from the Early versus Late Intervention Trial with Estradiol (ELITE).

Objective

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• Double blinded, placebo-controlled randomized clinical trial
• Tested whether the effect of hormone therapy (HT) on

atherosclerosis progression differed by time since menopause

• Healthy postmenopausal women without CHD, diabetes
• Oral micronized 17-beta-estradiol 1 mg/day

4% vaginal micronized progesterone gel 45 mg/day (10 days/month)

• Results
• Among early postmenopausal (< 6 years-since-menopause) women

HT significantly reduced CIMT progression

• Among late postmenopausal (≥ 10 years-since-menopause)

women HT had no effect on CIMT progression

ELITE

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Hodis HN, et al. Menopause. 2015;22(4):391-4 01.

• Study design and study population
• Cross-sectional and longitudinal analysis of trial data
• Postmenopausal women from the ELITE trial with available ApoE

genotype were included in the analysis (497 of 643)

• Subclinical atherosclerosis
• Common carotid artery intima media thickness (CIMT) measured

with B-mode ultrasound at baseline and every 6 months for 4.8 years

• ApoE4 genotype
• ApoE4 positive (E2/E4, E3/E4, E4/E4)
• ApoE4 negative (E2/E2, E3/E3, E2/E3)

Material and Methods

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• Metabolic phenotypes

A principal component analysis and K-means clustering analysis were used with baseline levels of 9 metabolic biomarkers.

Material and Methods

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Rettberg JR, et al. Neurobiol Aging. 2016;40:155-63. Mean values of each variable

• ANOVA and Chi-square test
• Compared baseline characteristics between ApoE4 genotype by

metabolic phenotype

• 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

Statistical Analysis

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Baseline characterist ics by metabolic phenotype

11 *Bolded numbers indicate significan t difference among phe notyp es (p<0.05).

Baseline characterist ics by metabolic phenotype and ApoE4 genotype

12 *Bolded numbers indicate significan t difference between ApoE4 geno type (p<0.05) **Red numbers indica te the highest values across gro ups

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Cross-sectional analysis Mean CIMT (SE) at baseline by metabolic phenotype and ApoE4 genotype

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• 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 Total sample 14 Early postmenopausal women < 6 years-since-menopause

Cross-sectional analysis Mean CIMT (SE) at baseline by metabolic phenotype and ApoE4 genotype

Late postmenopausal women ≥10 years-since-menopause ApoE4*metabolic phenotype interaction p = 0.05 ApoE4*metabolic phenotype interaction p = 0.02

Longitudinal analysis Mean CIMT (SE) progression by metabolic phenotype and ApoE4 genotype

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• ApoE4+ women with high blood

pressure phenotype and poor metabolic phenotype had the highest CIMT progression rate.

• ApoE4 genotype did not modify

the effect of metabolic phenotype on CIMT.

ApoE4*metabolic phenotype*time interaction p = 0.79 Total sample

• The adverse impact of metabolic dysregulation on CIMT

is modified by ApoE4 genotype.

• The impact was apparent only in women with ApoE4 positive

genotype.

• This modifying effect was found only in cross-sectional

but not longitudinal analysis.

• Baseline effect reflects long-term exposure effects and

cumulative progression of atherosclerosis.

• Inability to detect the longitudinal effect due to small sample size

and limited follow-up time.

Discussion

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• ApoE4 is also the major genetic risk factor for

Alzheimer’s disease.

• We have similarly shown the adverse impact of

metabolic dysregulation on cognition, specifically among ApoE4 positive women.

• ApoE4*metabolic phenotype interaction p = 0.003

Discussion

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Karim R, et al. Menopause. 2018.

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Conclusion

• ApoE4 positive women with poor metabolic phenotype

have higher levels of subclinical atherosclerosis.

• Identification of high risk women
• ApoE4 positive
• Elevated LDL, triglyceride, glucose, HbA1C, HOMA score
• Lowered HDL
• Preventive intervention strategies targeting high risk

women to reduce the burden of coronary heart disease.