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Genetic Epidemiology of Ankle Brachial Index and Peripheral Artery Disease in the Long Life Family Study

Ressler, Deidra Ann (2023) Genetic Epidemiology of Ankle Brachial Index and Peripheral Artery Disease in the Long Life Family Study. Master's Thesis, University of Pittsburgh. (Unpublished)

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The genetic influence on peripheral vascular health in exceptional aging has not been well studied. Thus, we calculated residual heritability, performed genome-wide linkage analyses (GWLA) and performed genome-wide association studies (GWAS) of ankle-brachial index (ABI) and peripheral artery disease (PAD) in 3006 individuals from the Long Life Family Study (LLFS). The LLFS is a longitudinal, family-based study including long-lived siblings and their families. ABI was measured in-home using an 8-mHz doppler ultrasound probe and an Omron 1300-HBP blood pressure cuff, and the minimum ABI from the left and right sides was used for analysis, with exclusions for ABI≥1.4 or non-compressible arteries. PAD was defined as ABI<0.9. We performed heritability and GWLA using SOLAR and GWAS using R while accounting for familial relationships. Our full model was adjusted for age, sex, site, significant PCs, blood pressure, and relevant risk factors including smoking, body size, and lipids. We considered significance at a LOD≥3.0 for GWLA and at a p<5E-8 for GWAS. The proband generation was 53.2% female, aged 88.7 and had a mean ABI of 1.06. The offspring generation was 60.1% female, aged 60.1 and had a mean ABI of 1.19. 18.2% of probands and 1.0% of offspring had PAD (7.4% overall). Residual genetic heritability was 0.12 (p=8.7E-4) for ABI and 0.23 for PAD (p=0.0662). We found linkage with chromosome 15q12 (LOD=3.65) for ABI, along with three genome-wide associations in offspring individuals on chromosome 1q12 (rs780213, p=4.02E-8; rs780211,p=5.54E-8; and rs2819869, p=6.7E-8). We also found an association on chromosome 4q25(rs12512857; p=6.25E10-8) for PAD in all individuals and on chromosome 17q25 (rs79644420,p=4.97E-8) in probands. This study suggests that genetic variation is associated with peripheral vascular health in long-lived families. By studying genetic factors related to peripheral vascular health in older adults, we may identify novel targets for future therapeutic interventions for susceptible individuals. Additionally, this study supports the importance of public health efforts in raising awareness of ABI as a meaningful screening tool to reduce critical limb ischemia, which can subsequently reduce annual healthcare spending.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Ressler, Deidra Annder94@pitt.eduder940009-0007-7247-2479
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKuipers, Allisonkuipersa@edc.pitt.edukuipersa
Committee MemberMinster, Ryanrminster@pitt.edurminster
Committee MemberZmuda, Josephzmudaj@edc.pitt.eduzmudaj
Date: 11 May 2023
Date Type: Publication
Defense Date: 30 March 2023
Approval Date: 11 May 2023
Submission Date: 18 April 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 101
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Epidemiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: epidemiology, peripheral artery disease, cardiovascular disease, longevity, aging, ankle brachial index
Date Deposited: 11 May 2023 16:23
Last Modified: 11 May 2023 16:23


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