allison kuipers 1, miljkovic i 1, kammerer cm 2, woodard g 1, bunker ch 1, patrick al 3, wheeler vw...

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Allison Kuipers 1 , Miljkovic I 1 , Kammerer CM 2 , Woodard G 1 , Bunker CH 1 , Patrick AL 3 , Wheeler VW 3 , Sutton-Tyrrell K 1 , Zmuda JM 1,2 1 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; 2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; 3 The 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, 2011 Marquis Marriott Hotel, Atlanta, GA Genome-Wide Linkage Analysis of Carotid Ultrasound Phenotypes in Afro-Caribbean Families

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Page 1: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 2: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 3: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 4: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 5: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 6: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 7: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 8: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

RESULTS

Page 9: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 10: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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)

Page 11: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 12: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

Genome-wide Linkage LOD Scores for IMT

RED line=mean IMT; BLUE line=max IMT

Page 13: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

Genome-wide Linkage LOD Scores for AD

RED line=mean AD; BLUE line=max AD

Page 14: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

Genome-wide Linkage LOD Scores for LD

RED line=mean LD; BLUE line=min LD

Page 15: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

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

Page 16: Allison Kuipers 1, Miljkovic I 1, Kammerer CM 2, Woodard G 1, Bunker CH 1, Patrick AL 3, Wheeler VW 3, Sutton-Tyrrell K 1, Zmuda JM 1,2 1 Department of

Thank You!