Allison L Kuipers1, Mary K Wojczynski2, Emma Barinas-Mitchell3, Ryan L Minster4, Lihua Wang2, Mary F Feitosa2, Alexander Kulminski5, Bharat Thyagarajan6, Joseph H Lee7, Michael A Province2, Anne B Newman3, Joseph M Zmuda8. 1. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: kuipers@pitt.edu. 2. Department of Genetics, Washington University in St Louis, St. Louis, MO, USA. 3. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA. 4. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. 5. Social Science Research Institute, Duke University, Durham, NC, USA. 6. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 7. Sergievsky Center, Taub Institute, Departments of Epidemiology and Neurology, Columbia University, New York, NY, USA. 8. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
Abstract
BACKGROUND AND AIMS: Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits. METHODS: Participants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age2, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR. RESULTS: All carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits. CONCLUSIONS: We identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging.
BACKGROUND AND AIMS: Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits. METHODS:Participants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age2, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR. RESULTS: All carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits. CONCLUSIONS: We identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging.
Authors: Kim Sutton-Tyrrell; Lewis H Kuller; Karen A Matthews; Richard Holubkov; Ami Patel; Daniel Edmundowicz; Anne Newman Journal: Atherosclerosis Date: 2002-02 Impact factor: 5.162
Authors: David Della-Morte; Liyong Wang; Ashley Beecham; Susan H Blanton; Hongyu Zhao; Ralph L Sacco; Tatjana Rundek; Chuanhui Dong Journal: J Neurol Sci Date: 2014-06-14 Impact factor: 3.181
Authors: Sayantan Das; Lukas Forer; Sebastian Schönherr; Carlo Sidore; Adam E Locke; Alan Kwong; Scott I Vrieze; Emily Y Chew; Shawn Levy; Matt McGue; David Schlessinger; Dwight Stambolian; Po-Ru Loh; William G Iacono; Anand Swaroop; Laura J Scott; Francesco Cucca; Florian Kronenberg; Michael Boehnke; Gonçalo R Abecasis; Christian Fuchsberger Journal: Nat Genet Date: 2016-08-29 Impact factor: 38.330
Authors: Janne Pott; Ralph Burkhardt; Frank Beutner; Katrin Horn; Andrej Teren; Holger Kirsten; Lesca M Holdt; Gerhard Schuler; Daniel Teupser; Markus Loeffler; Joachim Thiery; Markus Scholz Journal: Atherosclerosis Date: 2017-02-24 Impact factor: 5.162
Authors: Audrey Y Chu; Franco Guilianini; Harald Grallert; Josée Dupuis; Christie M Ballantyne; Bryan J Barratt; Fredrik Nyberg; Daniel I Chasman; Paul M Ridker Journal: Circ Cardiovasc Genet Date: 2012-11-01
Authors: Anne B Newman; Nancy W Glynn; Christopher A Taylor; Paola Sebastiani; Thomas T Perls; Richard Mayeux; Kaare Christensen; Joseph M Zmuda; Sandra Barral; Joseph H Lee; Eleanor M Simonsick; Jeremy D Walston; Anatoli I Yashin; Evan Hadley Journal: Aging (Albany NY) Date: 2011-01 Impact factor: 5.682
Authors: Joseph H Lee; Rong Cheng; Lawrence S Honig; Mary Feitosa; Candace M Kammerer; Min S Kang; Nicole Schupf; Shiow J Lin; Jason L Sanders; Harold Bae; Todd Druley; Thomas Perls; Kaare Christensen; Michael Province; Richard Mayeux Journal: Front Genet Date: 2014-01-17 Impact factor: 4.599
Authors: Nicole D Dueker; Ashley Beecham; Liyong Wang; Chuanhui Dong; Ralph L Sacco; Susan H Blanton; Tatjana Rundek Journal: PLoS One Date: 2022-01-12 Impact factor: 3.240
Authors: Mary K Wojczynski; Shiow Jiuan Lin; Paola Sebastiani; Thomas T Perls; Joseph Lee; Alexander Kulminski; Anne Newman; Joe M Zmuda; Kaare Christensen; Michael A Province Journal: J Gerontol A Biol Sci Med Sci Date: 2022-04-01 Impact factor: 6.053