Adam J. Beyer Dejan Miljkovic Michael Zöchling Stephanie Pirringer
Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW...
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Transcript of Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW...
Allison Kuipers1, Miljkovic I1, Kammerer CM2, Woodard G1, Bunker CH1, Patrick AL3, Wheeler VW3, Sutton-Tyrrell K1, Zmuda JM1,2
1Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA;2Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA;3The Tobago Health Studies Office, Scarborough, Tobago, West Indies
Presented at the 2011 NHLBI Trainee Session at the American Heart Association EPI/NPAM Conference
March 23, 2011Marquis Marriott Hotel, Atlanta, GA
Genome-Wide Linkage Analysis of Carotid Ultrasound Phenotypes in
Afro-Caribbean Families
Vessel Wall Physiology
Subclinical cardiovascular disease changes:
Intima layer thickens with atherosclerotic deposition
Adventitial diameter (AD) increases as vessel adapts to changes in hemodynamics
Lumen diameter (LD) increases with AD, but also decreases as large plaques occlude lumen
Ultrasound can image carotid artery and measures intima-media thickness (IMT), AD and LD
Associated with traditional CVD risk factors and predictive of future events and mortality
Carotid Ultrasound (US) Genetics
IMT: heritable, 4 genome-wide association or linkage studies, >300 candidate gene studies
AD and LD: less studied, unknown heritability, few genome-wide or candidate studies
Few studies in African ancestry populations
APOE lipoproteins/lipids chr 19, q13.2
ACE renin-angiotensin system chr 17, q23.3
MTHFR homocysteine metabolism chr 1, p36.3
NOS3 nitric oxide metabolitsm chr 7, q36
ADD1 vessel wall structure chr 4, p16.3
9p21.3 unknown function chr 9, p21.3
To perform genome-wide linkage analysis on common carotid artery traits (IMT, AD and LD) from carotid ultrasound in African ancestry families from the Tobago Family Study.
PURPOSE
Tobago Family Study
Extended families: 471 individuals (187
men, 284 women) in 7 families
Afro-Caribbean ancestry
Aged 18-92
Subclinical CVD visit: common carotid artery
ultrasound scan
N = 395
Carotid Ultrasound
B-mode ultrasonography by Acuson Cypress portable machine
Near and far walls of CCA (1cm distal to carotid bulb)
right and left sides had 2 images per side (4 images)
read using semi-automated reading software
Mean, max (IMT, AD) and min (LD) traits were analyzed
Statistics and Linkage Analysis
Covariate model building and proportion of variance due to genetics (heritability) and covariates (SOLAR)
Genotyped panel of SNPs from genomic DNA
Applied quality control filters resulting in 1,512 SNPS spaced ~1.92 cM across genome
Calculated multipoint IBD (Loki); ran QTL linkage analysis (SOLAR) on fully adjusted traits
Suggestive and significant evidence of linkage set at LOD > 2.0 and > 3.3, respectively
RESULTS
Trait All (n=395) Men (n=152) Women (n=243)Age (years) 42.1 ± 15.7 42.2 ± 15.4 42.1 ± 15.9
BMI (kg/m2) 28.4 ± 6.3 26.8 ± 5.1‡ 29.5 ± 6.7‡
Height (cm) 170.5 ± 8.3 177.1 ± 6.8‡ 166.4 ± 6.3‡
Waist Circumference (cm) 89.7 ± 15.3 90.3 ± 12.9 89.4 ± 16.7
Current Smoker (%) 4.3 10.7‡ 0.4‡
>1 Drink per week (%) 12.7 29.1‡ 2.5‡
≥25 Min walk per week (%) 48.5 53.0 45.7
Diabetes (%) 8.3 6.4 9.4
Hypertension (%) 26.6 27.8 25.8
Hypertensive Medication (%) 8.4 4.0‡ 11.1‡
Systolic Blood Pressure (mmHg)§ 118.8 ± 21.8 125.7 ± 19.5‡ 114.1 ± 22.1‡
LDL-c (mg/dl) 132.8 ± 40.1 126.9 ± 37.5‡ 136.5 ± 41.3‡
HDL-c (mg/dl) 39.8 ± 12.3 40.7 ± 11.6 39.2 ± 12.7
Triglycerides (mg/dl) 88.9 ± 44.9 96.2 ± 54.1‡ 84.5 ± 37.6‡
Menopausal (%)† 30.1 -- 30.1
Parity (%)† 77.0 -- 77.0Oral Contraceptive (%)† 34.4 -- 34.4
§Excluding participants on hypertensive medication†Frequency in women only‡Comparison by sex is statistically significant (p<0.05)
Characteristics of the Afro-Caribbean Family Members
Ultrasound Traits in the Afro-Caribbean Family Members
Trait All Men Women
Mean IMT (mm)
0.69 ± 0.15 0.70 ± 0.15 0.68 ± 0.14
Max IMT (mm) 0.80 ± 0.17 0.81 ± 0.17 0.79 ± 0.16Mean AD (mm) 7.23 ± 0.72 7.49 ± 0.68‡ 7.07 ± 0.70‡
Max AD (mm) 7.53 ± 0.76 7.78 ± 0.74‡ 7.36 ± 0.74‡
Mean LD (mm) 5.86 ± 0.64 6.09 ± 0.63‡ 5.71 ± 0.61‡
Min LD (mm) 5.65 ± 0.64 5.89 ± 0.62‡ 5.51 ± 0.61‡‡Comparison by sex is statistically significant (p<0.05)
Carotid Ultrasound Traits Variance Components
Trait Significant Covariates*Covariate
Effects (r2)
Genetic Effects
(h2r SE)¥
Mean IMT age, (-) female sex, BMI, SBP
0.552 0.467±0.110
Max IMT age, BMI, SBP 0.564 0.349±0.101Mean AD age, height, waist, SBP 0.245 0.641±0.120Max AD age, height, waist, SBP 0.270 0.622±0.127Mean LD (-) age, height, waist, SBP 0.169 0.584±0.123Min LD (-) age, height, waist, SBP 0.182 0.573±0.120
* Sex forced into all final models, even when not significant predictor alone¥ All residual heritability estimates had a corresponding P-value < 0.0001
Genome-wide Linkage LOD Scores for IMT
RED line=mean IMT; BLUE line=max IMT
Genome-wide Linkage LOD Scores for AD
RED line=mean AD; BLUE line=max AD
Genome-wide Linkage LOD Scores for LD
RED line=mean LD; BLUE line=min LD
Conclusions
All US traits were heritable in this African ancestry family population Future study of genetics of vessel diameter warranted
Evidence of linkage identified for AD/LD on chr. 11 Genes w/ known CVD implications: APOA1/C3/A4/A5 and
IL18
Suggestive linkage on chr. 13 (IMT) and 14 (AD/LD) No genes w/ strong CVD implications
Further refinement of linkage peaks needed
Thank You!