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Haijar, Ihab MD, MS, Kritchevsky, S PhD., et al.

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

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Haijar, Ihab MD, MS, Kritchevsky, S PhD., et al.

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  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. 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

  4. 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

  5. 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

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

  7. 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

  8. 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

  9. 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)

  10. 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

  11. 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

  12. Resources • "ACE Inhibitor." Wikipedia, the Free Encyclopedia. 03 Feb. 2012. Web. 09 Feb. 2012. http://en.wikipedia.org/wiki/ACE_inhibitor>. • "Angiotensin-converting Enzyme." Wikipedia, the Free Encyclopedia. 23 Jan. 2012. Web. 09 Feb. 2012. http://en.wikipedia.org/wiki/Angiotensin_converting_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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