Renin Angiotensin System Gene Polymorphisms Modify Angiotensin-Converting Enzyme and Inhibitors' Effect on Cognitive Decline: The Health, Aging and Body Composition Study - PowerPoint PPT Presentation

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Renin Angiotensin System Gene Polymorphisms Modify Angiotensin-Converting Enzyme and Inhibitors' Effect on Cognitive Decline: The Health, Aging and Body Composition Study

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Title: Renin Angiotensin System Gene Polymorphisms Modify Angiotensin-Converting Enzyme and Inhibitors' Effect on Cognitive Decline: The Health, Aging and Body Composition Study


1
Renin Angiotensin System Gene Polymorphisms
Modify Angiotensin-Converting Enzyme and
Inhibitors' Effect on Cognitive Decline The
Health, Aging and Body Composition Study
  • Haijar, Ihab MD, MS, Kritchevsky, S PhD., et al.

Khalil Khlifi Pharm D. Candidate 2012 University
of Georgia, College of Pharmacy
2
Angiotensin-Converting Enzyme Inhibitors
  • Primarily used in the treatment of hypertension,
    congestive heart failure, and diabetic
    nephropathy
  • Originally, derived from pit viper toxin and was
    seen to decrease tension of blood vessels thereby
    lower blood pressure
  • Pharmacologically, ACE-I block the conversion of
    Angiotensin I to Angiotensin II
  • Lowers arteriolar resistance
  • Increase Venous capacity
  • Increases cardiac output, stroke work and volume
  • Lower renovascular resistance
  • Increase natriuresis 

3
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4
Polymorphisms present in Angitotensin
  • Angiotensinogen gene (AGT)
  • Codes angiotensinogen protein
  •  M235T
  • 6AG
  • Angiotensin-converting enzyme gene (ACE)
  • Codes ACE protein
  • ACEID
  • Both are involved in the production of
    angiotensin II

5
Angiotensin Converting Enzyme (ACE)
  • ACEID (angiotensin-converting enzyme insertion
    deletion)
  • 287 base pairs inserted/deleted in intron 16
  • DD genotype is associated with higher levels of
    plasma ACE
  • DD, ID, II are the three allele combinations

6
Angiotensinogen gene (AGT)
  • M235T is a nucleotide change from methionine to
    threonine at position 235
  • C allele is associated with higher
    angiotensinogen levels
  • CC, CT, TT are the three allele combinations
  • 6AG is a nucleotide change of guanine to adenine
    in the promoter region
  • A allele is associated with higher
    angiotensinogen levels
  •  AA, AG, GG are the three allele combinations
  • Both may attribute to higher renin angiotensin
    system activity

7
Study Population
  • 58 Caucasian
  • 52 female
  • 15 were receing ACE-I previously
  • Average age 73.6
  • 3075 participants and 2974 received genotyping

8
Statistical Analysis
  • Hardy-Weinburg Equilibrium testing was conducted
    using SAS/Genetics
  • Significant difference in alleles were found
    between caucasian and african americans so they
    were further stratified according to race for
    analysis
  • ANOVA was used to compare baseline cognitive
    scores between the three genotypes of the
    polymorphisms using data from Y1 for 3MSE and
    DSST and Y3 for CLOX1
  • Least square mean were used to compare the change
    during the follow-up period in the cognitive
    scores between those taking and not taking ACE-I
    in the three genotypes

9
Least Square Mean
  • Also known as estimated marginal mean
  •  Takes into consideration the mean of each group
    due to the unproportional group size
  • Each mean is looked at proportionally compared to
    the sample size of each group and adjusted for
    the disparity in sample size
  • This is done by applying weights to each group
    that standardize each group based on the sample
    size and the mean

10
Results/Discussion
  • At baseline, there was no interaction between the
    genetic polymorphisms and ACE-I exposure in
    either racial group
  • Longitudinaly, 6AG and M235T had significant
    interactions with ACE-I with change to CLOX1
    scores in Caucasian participants (p.01 for 6AG
    and .01 for M235T)
  • Less decline in CLOX1 score over follow up period
    in those with the AA allele (6AG) and CC allele
    (M235T)
  • More decline in CLOX1 score over follow up period
    in those with the AG and GG genotypes of the 6AG
    and the CT genotype of the M235T only if not
    exposed to ACE-I (Caucasion but not African
    Americans)

11
Results/Discussion
  • ACEID did not modify the effect of ACE-I on
    dementia or cognitive function
  • Racial difference was observed in the association
    between the polymorphism and cognitive function
    and the interaction with ACE-I, with results
    significant only in caucasians
  • Mechanism of ACE-I and improvement in cognition
    is unknown but may be due to some vascular
    protection of the brain or some reduction in
    inflammatory biomarkers
  • Limitations confounding by indication with
    people with higher risk for cognitive decline not
    being prescribed ACE-I

12
Conclusion
  • There may be some benefit of ACE-I in caucasian
    patients with the following genotypes
  • AA, AG, GG of 6AG
  • CC and CT genotype in M235T
  • There is additional benefit to continue funding
    these types of clinical trials

13
Resources
  • "ACE Inhibitor." Wikipedia, the Free
    Encyclopedia. 03 Feb. 2012. Web. 09 Feb. 2012.
    http//en.wikipedia.org/wiki/ACE_inhibitorgt.
  • "Angiotensin-converting Enzyme." Wikipedia, the
    Free Encyclopedia. 23 Jan. 2012. Web. 09 Feb.
    2012. http//en.wikipedia.org/wiki/Angiotensin_con
    verting_enzyme.
  • Hajjar, Ihab, Stephen Kritchevsky, Anne B.
    Newman, Rongling Li, Kristine Yaffe, Eleanor M.
    Simonsick, and Lewis A. Lipsitz. "Renin
    Angiotensin System Gene Polymorphisms Modify
    Angiotensin-Converting Enzyme Inhibitors' Effect
    on Cognitive Function The Health, Aging and Body
    Composition Study." Journal of the American
    Geriatrics Society 58.6 (2010) 1035-042. Print.
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