Transcript Functional Variants in Platelet Receptor Genes are

Functional Variants in Platelet
Receptor Genes are Associated
with Carotid Intima-Media
Thickness in Healthy Adults
Jennifer N. Cooper1, Maria Mori Brooks1,2, Joseph M. Zmuda1,3, Rhobert W.
Evans1, Chris Holmes4, Kim Sutton-Tyrrell1
1Departments
of Epidemiology, 2Biostatistics, and 3Human Genetics, Graduate School of
Public Health, University of Pittsburgh
4Colchester Research Facility, University of Vermont College of Medicine
1
Background
• Platelets play key role in atherosclerosis
• ↑ platelet activation associated with ↑ carotid intimamedia thickness (IMT)
• Platelet activation ↑ in obesity and ↓ with weight loss
Gawaz et al. J Clin Invest. 2005.;115: 3378-84.
2
Platelet Receptors
Jennings. Thromb Haemost. 2009; 102: 248–57.
3
SAVE Trial
• RCT assessing impacts of weight loss and reduced
sodium intervention on vascular health
• Goals
– 10% weight loss
– ↑ in weekly activity of 150 minutes
• Randomized to low sodium or control sodium
lifestyle intervention
• Evaluated CVD risk factors and non-invasive vascular
measures at baseline and 6, 12, and 24 months
4
Study population
• Overweight or obese adults aged 20-45 (n=349)
• Exclusion criteria
–
–
–
–
Physically active
Diabetic
Hypertensive
Cholesterol lowering, anti-psychotic, vasoactive meds;
vasoactive devices
– Pregnant or breast feeding
• Genetic study (N=266 white, N=50 black)
• Sub-study of platelet activity (N=88)
5
Hypotheses
• SNPs are associated with segment-specific IMT
• Lifestyle modification eliminates these associations
• ↓ circulating platelet activity associated with
– ↓ IMT
– Weight loss
6
Methods
• Baseline
– Common carotid, carotid bulb,
and internal carotid IMT
• Follow-up
– Common carotid IMT
– β-thromboglobulin (β-TG)
7
Statistical Analyses
•
•
•
•
Dominant genetic model, stratified by race
ANCOVA
Linear Mixed Effects Models
Spearman correlations and multiple linear
regression
• False discovery rate (FDR)
8
Baseline Characteristics
Characteristic
Total (N=316)
White Non-
Black Non-
Hispanic (N=266)
Hispanic (N=50)
Age (years)
37.9 (6.1)
37.9 (6.3)
38.2 (5.3)
Women (n, %)
246 (77.9)
199 (74.8)
47 (94.0)
BMI (kg/m2)
32.9 (3.9)
32.9 (4.0)
33.0 (3.5)
SBP (mmHg)
113.5 (10.5)
113.1 (10.1)
115.4 (12.3)
HDL-C (mg/dL)
52.8 (13.6)
51.6 (12.6)
59.1 (17.0)
114.5 (78, 169)
121 (82, 175)
80 (64, 119)
Mean Internal Carotid IMT (mm)
0.57 (0.15)
0.57 (0.15)
0.56 (0.17)
Mean Carotid Bulb IMT (mm)
0.69 (0.16)
0.68 (0.16)
0.71 (0.17)
Mean CCA IMT (mm)
0.60 (0.08)
0.59 (0.07)
0.64 (0.11)
Triglycerides (mg/dL)
9
Baseline IMT by rs168753 (PAR-1)
Genotype
0.8
IMT (mm)
0.7
AA (N=190)
AT/TT (N=75)
AA (N=40)
AT/TT (N=9)
**
*
0.6
0.5
0.4
0.3
Whites
Blacks
Mean ICA IMT
Whites Blacks
Mean Bulb IMT
Whites
Blacks
Mean CCA IMT
10
Longitudinal Changes in CCA IMT by
rs168753 (PAR-1) Genotype
Whites
Blacks
11
Platelet activity and CVD risk factors
Variable
r (p)
Waist circumference
0.25 (0.02)
LDL-C
0.29 (0.006)
HDL-C
-0.17 (0.11)
Triglycerides
0.23 (0.03)
CRP
0.09 (0.39)
SBP
0.05 (0.66)
Insulin
0.08 (0.48)
CCA IMT
0.07 (0.54)
12
Platelet Activity and Weight Loss
β = -0.048, p=0.046
13
Conclusions
• T allele carriers of rs168753
– ↑ baseline carotid bulb IMT in whites
– Greater ↑ in CCA IMT over one year in blacks
• Possible association between this SNP and platelet function
• PAR-1 is important in intimal proliferation, inflammation
• Lower circulating platelet activity
– ↓ concurrent body size, ↓ concurrent LDL-C and triglycerides
– Greater ↓ in body size during intervention
• Platelet activation may be associated with IMT only in more
advanced atherosclerosis
• Platelet activation remains lowered after successful lifestyle
modification
14
Limitations
• Small sample size
• Not all measures performed
longitudinally
15
Strengths
• Longitudinal study
• Normotensive participants; no use of
medications affecting the vasculature
16
Thank you!
Grant Support: R01 HL077525-01A2, T32 HL083825-01 (NHLBI)
17
EXTRA SLIDES
18
Intervention Results
6 Months
12 Months
(N=261)
(N=233)
Weight (kg)
-6.8 (6.1)
-6.2 (7.3)
SBP (mmHg)
-2.7 (8.1)
-2.9 (8.2)
-19 (-43, 8)
-18 (-51, 7)
-0.8 (-3.6, 1.6)
-0.8 (-3.8, 2.3)
0.003 (0.04)
0.01 (0.05)
Variable
Triglycerides (mg/dL)
Insulin (µU/mL)
Mean CCA IMT (mm)
19
Intervention Results by Race
Whites
Blacks
Six
Twelve
Six
Twelve
Months
Months
Months
Months
(N=224)
(N=199)
(N=40)
(N=34)
Weight (kg)
-7.1 (6.2)
-6.3 (7.5)
-5.2 (5.3)
-5.6 (6.2)
SBP (mmHg)
-3.0 (8.1)
-3.2 (8.1)
-1.2 (8.4)
-1.3 (8.6)
-20 (-47, 7)
-19.(-54., 7)
-2.5 (-31. 11.5)
-17 (-27, 6.5)
-0.7 (-3.5, 1.8)
-0.5 (-3.0, 2.4)
-2.0 (-4.9, 1.2)
-2.8 (-5.0, 0.7)
0.004 (0.04)
0.009 (0.05)
-0.002 (0.05)
0.017 (0.07)
Variable
Triglycerides (mg/dL)
Insulin (µU/mL)
Mean CCA IMT (mm)
20
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