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Genome-Wide Linkage Analysis of Carotid Ultrasound Phenotypes in Afro-Caribbean Families

Genome-Wide Linkage Analysis of Carotid Ultrasound Phenotypes in Afro-Caribbean Families. 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

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Genome-Wide Linkage Analysis of Carotid Ultrasound Phenotypes in Afro-Caribbean Families

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  1. Genome-Wide Linkage Analysis of Carotid Ultrasound Phenotypes in Afro-Caribbean Families 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, 2011 Marquis Marriott Hotel, Atlanta, GA

  2. 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

  3. 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

  4. PURPOSE 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.

  5. 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

  6. 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

  7. 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

  8. RESULTS

  9. Characteristics of the Afro-Caribbean Family Members §Excluding participants on hypertensive medication †Frequency in women only ‡Comparison by sex is statistically significant (p<0.05)

  10. Ultrasound Traits in the Afro-Caribbean Family Members ‡Comparison by sex is statistically significant (p<0.05)

  11. Carotid Ultrasound Traits Variance Components * Sex forced into all final models, even when not significant predictor alone ¥ All residual heritability estimates had a corresponding P-value < 0.0001

  12. Genome-wide Linkage LOD Scores for IMT RED line=mean IMT; BLUE line=max IMT

  13. Genome-wide Linkage LOD Scores for AD RED line=mean AD; BLUE line=max AD

  14. Genome-wide Linkage LOD Scores for LD RED line=mean LD; BLUE line=min LD

  15. 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

  16. Thank You! Acknowledgements: Zmuda Lab (genotyping) Cara Nestlerode, MS Ashley Edwards, BS Linkage Analysis Amy Dressen, MS Ryan Minster, MS Hu Li, PhD Ultrasound Study Set-Up Genevieve Woodard, PhD Mentors Joseph Zmuda, PhD Candace Kammerer, PhD Kim Sutton-Tyrrell, PhD Clareann Bunker, PhD Iva Miljkovic, PhD Funding NHLBI: T32-HL083825 NIAMS: R03-AR050107 and R01-AR049747 No Disclosures

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