Transcript WHI BAA-24 short powerpoint

WHI BAA-24: Metabolomics of
CHD in the WHI
PI: Kathryn Rexrode, MD, MPH
Brigham and Women’s Hospital
[email protected]
WHI Genetics SIG, May 22, 2013
Background
• Many of the strongest risk factors for CVD in women are associated with
altered metabolism, but exactly how these metabolic perturbations
directly impact the pathophysiology of CHD is not clear.
• Metabolite profiling techniques (metabolomics) provide a tool for
measuring a full profile of small-molecule metabolites, providing a
comprehensive picture of an individual’s metabolic status.
• These methods have been applied by our group (Clary Clish) to identify a
panel of metabolites that predicted incident diabetes over 12 years.
(Wang T, et al. Nat Med 2011;17:448-453.)
• Although preliminary results for CHD are promising, only small studies
with short duration of follow-up have examined these compounds
prospectively for CHD.
• This project will measure a well-validated metabolomic profile, and test
specific metabolic hypotheses for incident CHD. In addition, the proposal
will examine how hormone therapy (HT) changes metabolomic profiles,
and whether these changes explain the increased risk observed for
combined HT.
Specific Aims
1. To test individual metabolite and metabolomic profiles associated with incident
CHD in women. (Using 400 CHD cases and 400 controls in the WHI-OS, with replication
among the 342 cases and 342 controls in the WHI-HT placebo arms).
a) To test specific metabolic hypotheses regarding CHD, including Branched-chain amino
acids (AA) and aromatic AA, small and medium-chain acylcarnitines, metabolites of dietary
phosphotidylcholine, urea cycle metabolite, and desaturation of lipids.
b) Agnostic examination of metabolites and metabolomic profiles associated with CHD.
2. To compare changes in metabolomic profiles from baseline to year 1 in E-alone,
E+P and placebo controls in the WHI-HT, and to test whether these changes
explain the increased risk of CHD with E+P, but not E alone, in the HT trials.
3. To explore the relationship of metabolomic profiles with previously measured
clinical parameters, biomarkers and genomic data. (Including blood pressure,
waist circumference, body mass index,markers of lipoproteins, inflammation,
endothelial function, insulin resistance and thrombosis/fibrinolysis, as well as
genomic data).
Specific metabolite hypotheses
Table 2. Specific hypotheses and metabolites to be tested in this proposal.
Specific hypotheses associated with CHD
Metabolites
Branched-chain amino acids (CAA) and aromatic
amino acids (AAA)
Small and medium-chain acylcarnitines
BCAA: leucine, isoleucine, and valine
AAA: phenylalanine and tyrosine
Acylcarinitines and dicarboxylacylcarinitines
Metabolites of dietary phosphotidylcholine
Urea cycle metabolites
Trimethylamine N-oxide [TMAO], as well as
choline, and betaine
Arginine, histidine, and citrulline
Desaturation of lipids
Triacylglycerols
An agnostic evaluation of the complete metabolomic profile (>300 metabolites)
will also be performed using principal component analysis, as well as network and
pathway approaches.
Study Overview
• Metabolomic profiles of >300 metabolites will be measured at Broad
Institute (Clary Clish) on a total of 2210 women in the WHI (1105 cases
and 1105 controls) using a nested case-control design and building upon
prior datsets used for biomarker and GWAS studies whenever possible.
• Baseline profiles will be measured on enrollment samples from 400
incident CHD cases and 400 controls in the WHI-OS, and on all CHD cases
and controls from the WHI-HT trials both at WHI enrollment and year 1.
• A two-phase analysis will be conducted with a “discovery cohort” of 400
CHD cases in the WHI-OS, and a “validation cohort” using the 342 CHD
cases and matched controls among the placebo arm of the WHI HT trials.
• The effect of HT on metabolomic profiles from baseline to year 1 will be
compared in estrogen plus progestin (E+P), estrogen alone (E-alone) and
placebo arms, and then the degree to which this mediates the observed
risk of CHD with E+P will be tested.
• Metabolomic data will be integrated with prior clinical, biomarker and
genomic data from each of these cohorts using network and pathways
approaches.
Study design according to specific aim
Specific Aim
Substudy
Analysis
Sample year
Cases/ controls
Aim 1- initial
WHI-OS
Risk of CHD (initial)
WHI baseline
400/400
Aim 1-validation
WHI-HT
Risk of CHD (validation)
WHI baseline
342/342 placebo arms
(baseline also used for 2b)
Aim 2 a
Aim 2b
Aim 3
WHI-HT
WHI-HT
All metabolomics
samples
Metabolomic change
with HT
baseline; Year-1
Metabolomic change
mediation of CHD risk
Year-1
Network analyses of
metabolomics, clinical
data, biomarkers and
genomic data
WHI baseline;
Year-1
363/363 active arms
363/363 active arms
227/227 placebo arms
Variable
(1105/1105)
Aim 1 will involved a total of 1632 samples (400 pairs of participants from baseline OS and 342 pairs of participants from
HT-placebo arms, plus 10% QC).
Aim 2 will involve a total of 2849 samples (including 752 baseline samples already measured in aim1). A total of 363 pairs
of participants in the HT-active arms for both baseline and year 1 (1597 samples including QC) and 227 pairs of participants
in the HT-placebo arms for year 1 measures (500 samples including QC) will be measured for aim 2.
Aim 3 will utilize all 3729 samples that will be measured in the proposal.
Potential impact of the study
• By focusing on molecules that are proximate in the biologic
causal pathway, perhaps direct mediators of CHD risk, the
likelihood of identifying pharmacologic targets is increased.
• Understanding differences in metabolomic profiles between
the two hormone therapy arms in the WHI-CT, and whether
these differences might mediate impact the difference in CHD
risk between the two arms, may have direct clinical
implications.
• The proposed study:
– is of substantially larger size than prior metabolomic studies,
– will test a large panel of well-validated metabolites, and
– will focus on women who may have substantial differences in levels
than men due to sex hormone or other sex-related factors.
Investigative team
• Brigham and Women’s • Broad Institute:
Hospital:
Clary Clish, PhD
Kathy Rexrode, MD, MPH • University of
Christine Albert, MD, MPH
Massachusetts:
JoAnn Manson, MD, DrPH
Raji Balasubramanian, ScD
Nina Paynter, ScD
• Fred Hutchinson/ WHINancy Cook, ScD
CCC:
Lesley Tinker, PhD