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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.

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Presentation on theme: "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."— Presentation transcript:

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 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

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 APOElipoproteins/lipidschr 19, q13.2 ACErenin-angiotensin systemchr 17, q23.3 MTHFRhomocysteine metabolismchr 1, p36.3 NOS3nitric oxide metabolitsmchr 7, q36 ADD1vessel wall structurechr 4, p16.3 9p21.3unknown functionchr 9, p21.3

4 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

5 Tobago Family Study Extended families:  471 individuals (187 men, 284 women) in 7 families  Afro-Caribbean ancestry  Aged 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 TraitAll (n=395)Men (n=152)Women (n=243) Age (years)42.1 ± ± ± 15.9 BMI (kg/m 2 )28.4 ± ± 5.1 ‡ 29.5 ± 6.7 ‡ Height (cm)170.5 ± ± 6.8 ‡ ± 6.3 ‡ Waist Circumference (cm)89.7 ± ± ± 16.7 Current Smoker (%) ‡ 0.4 ‡ >1 Drink per week (%) ‡ 2.5 ‡ ≥25 Min walk per week (%) Diabetes (%) Hypertension (%) Hypertensive Medication (%) ‡ 11.1 ‡ Systolic Blood Pressure (mmHg) § ± ± 19.5 ‡ ± 22.1 ‡ LDL-c (mg/dl)132.8 ± ± 37.5 ‡ ± 41.3 ‡ HDL-c (mg/dl)39.8 ± ± ± 12.7 Triglycerides (mg/dl)88.9 ± ± 54.1 ‡ 84.5 ± 37.6 ‡ Menopausal (%) † Parity (%) † Oral Contraceptive (%) † § 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

10 Ultrasound Traits in the Afro-Caribbean Family Members TraitAllMenWomen Mean IMT (mm)0.69 ± ± ± 0.14 Max IMT (mm)0.80 ± ± ± 0.16 Mean AD (mm)7.23 ± ± 0.68 ‡ 7.07 ± 0.70 ‡ Max AD (mm)7.53 ± ± 0.74 ‡ 7.36 ± 0.74 ‡ Mean LD (mm)5.86 ± ± 0.63 ‡ 5.71 ± 0.61 ‡ Min LD (mm)5.65 ± ± 0.62 ‡ 5.51 ± 0.61 ‡ ‡ Comparison by sex is statistically significant (p<0.05)

11 Carotid Ultrasound Traits Variance Components TraitSignificant Covariates* Covariate Effects (r 2 ) Genetic Effects (h 2 r  SE) ¥ Mean IMT age, (-) female sex, BMI, SBP ±0.110 Max IMT age, BMI, SBP ±0.101 Mean AD age, height, waist, SBP ±0.120 Max AD age, height, waist, SBP ±0.127 Mean LD (-) age, height, waist, SBP ±0.123 Min LD (-) age, height, waist, SBP ±0.120 * Sex forced into all final models, even when not significant predictor alone ¥ All residual heritability estimates had a corresponding P-value <

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 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-HL NIAMS: R03-AR and R01-AR No Disclosures Thank You!


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