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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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
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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 

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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

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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

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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

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Study Population

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

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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

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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

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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)

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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

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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

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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.