GENETIC EPIDEMIOLOGY OF AGING IN UTAH PEDIGREES

Summary

Principal Investigator: Steven Hunt
Affiliation: University of Utah
Country: USA
Abstract: DESCRIPTION: (provided by applicant) One aspect of aging that leads to the most common forms of morbidity and mortality is the aging of the vascular system. One of the most important processes involves the balance between the oxidative burden seen by the vasculature and the capacity of antioxidants to counteract that burden. Telomere length is also closely related to vascular aging, measuring biological age rather than chronological age. Telomeres determine processes related to cellular and DNA repair, cellular replicative capacity, and apoptosis. Shorter telomeres have been associated with decreased longevity and increased pulse pressure and cardiovascular disease. In addition, oxidant/antioxidant balance appears to play an important role in regulating the length of telomeres. Although the individual effects of each system have been studied in vitro and in small samples of human subjects, their individual and interactive effects have not been studied in large population cohorts to assess their influence on vascular aging and morbidity. One of the aims of this grant is to relate these two systems to comprehensive measures of vascular dysfunction and aging in a 22-year longitudinally followed cohort of 1500 relatives in 98 large Utah pedigrees. These comprehensive measures assess aging in multiple vascular beds and include small and large artery stiffness/compliance, carotid intima-media thickness, coronary and abdominal aortic calcium levels, endothelial function (flow mediated dilation), peripheral artery disease, and pulse pressure. Multiple measures of baseline and 22-year rates of change in total antioxidant capacity, indicators of total oxidant stress, and telomere length will be related to these subclinical aging indicators. Because pedigrees are being studied which already have genome search markers genotyped, some of the underlying genes contributing to the expression of the above phenotypes may be localized by linkage and identified through pedigree-based haplotype association analyses. Evidence of significant linkage for multiple antioxidants and other indicators of aging have been found in these pedigrees, and the underlying genes will be pursued and related to the subclinical vascular measures. This collection of longitudinally followed pedigrees provides a powerful study design to address a wide range of genetic epidemiological analyses of aging.
Funding Period: 2000-09-30 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. pmc Strategies to improve detection of hypertension genes
    Steven C Hunt
    Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84108, USA
    J Nutrigenet Nutrigenomics 3:182-91. 2010
  2. pmc Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol
    Brian H Shirts
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
    Atherosclerosis 222:167-74. 2012
  3. doi Effects of ethanol intake on lipoproteins
    Eliot A Brinton
    Utah Foundation for Biomedical Research, Salt Lake City, UT, USA
    Curr Atheroscler Rep 14:108-14. 2012
  4. pmc The epithelial sodium channel γ-subunit gene and blood pressure: family based association, renal gene expression, and physiological analyses
    Cara J Büsst
    Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
    Hypertension 58:1073-8. 2011
  5. pmc Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR
    Abraham Aviv
    The Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA
    Nucleic Acids Res 39:e134. 2011
  6. pmc Meta-analysis of genome-wide linkage scans for renal function traits
    Madhumathi Rao
    Division of Nephrology, Tufts Medical Center, Boston, MA, USA
    Nephrol Dial Transplant 27:647-56. 2012
  7. pmc Evaluation of the gene-age interactions in HDL cholesterol, LDL cholesterol, and triglyceride levels: the impact of the SORT1 polymorphism on LDL cholesterol levels is age dependent
    Brian H Shirts
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
    Atherosclerosis 217:139-41. 2011
  8. doi Effects of ethanol intake on lipoproteins and atherosclerosis
    Eliot A Brinton
    Department of Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA
    Curr Opin Lipidol 21:346-51. 2010
  9. pmc Genetic architecture of complex traits predisposing to nephropathy: hypertension
    Steven C Hunt
    Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Semin Nephrol 30:150-63. 2010
  10. doi Two-dimensional, sex-specific autosomal linkage scan of the number of sodium pump sites
    Sandra J Hasstedt
    Department of Human Genetics, University of Utah School of Medicine, University of Utah, Salt Lake City, Utah 84112, USA
    J Hypertens 28:740-7. 2010

Scientific Experts

  • Brian H Shirts
  • Eliot A Brinton
  • Steven Hunt
  • SANDRA HASSTEDT
  • Hilary Coon
  • A Aviv
  • Paul N Hopkins
  • Madhumathi Rao
  • Cara J Büsst
  • Arno Lingenhel
  • Barry I Freedman
  • Sudha K Iyengar
  • Jason G Umans
  • Caroline S Fox
  • Amy K Mottl
  • Carl D Langefeld
  • Shelley A Cole
  • Qiong Yang
  • Adrienne Cupples
  • Donald W Bowden
  • Thomas A Trikalinos
  • Maciej Tomaszewski
  • Timothy A Barnes
  • Justine A Ellis
  • Stephen B Harrap
  • Peter Braund
  • Lisa D S Bloomer
  • Nilesh J Samani
  • Katrina J Scurrah
  • Fadi J Charchar
  • Johannes P Schwaiger
  • Veit Schoenborn
  • Florian Kronenberg
  • Iris M Heid
  • Richard Gress
  • Barbara Kollerits

Detail Information

Publications15

  1. pmc Strategies to improve detection of hypertension genes
    Steven C Hunt
    Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84108, USA
    J Nutrigenet Nutrigenomics 3:182-91. 2010
    ..Genes found to be significant in such studies should be densely typed in clinical trials and large population studies to assess public health and clinical applications of the findings...
  2. pmc Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol
    Brian H Shirts
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
    Atherosclerosis 222:167-74. 2012
    ..Vitamin D and serum lipid levels are risk factors for cardiovascular disease. We sought to determine if vitamin D (25OHD) interacts at established lipid loci potentially explaining additional variance in lipids...
  3. doi Effects of ethanol intake on lipoproteins
    Eliot A Brinton
    Utah Foundation for Biomedical Research, Salt Lake City, UT, USA
    Curr Atheroscler Rep 14:108-14. 2012
    ..Application of these findings in clinical practice remains problematic, however, due to the lack of randomized, controlled clinical trials of ethanol and due to the potential hazards of ethanol consumption...
  4. pmc The epithelial sodium channel γ-subunit gene and blood pressure: family based association, renal gene expression, and physiological analyses
    Cara J Büsst
    Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
    Hypertension 58:1073-8. 2011
    ..07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination...
  5. pmc Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR
    Abraham Aviv
    The Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA
    Nucleic Acids Res 39:e134. 2011
    ..We discuss the ramifications of these findings with regard to measurements of telomere length/DNA content in epidemiological/clinical circumstances...
  6. pmc Meta-analysis of genome-wide linkage scans for renal function traits
    Madhumathi Rao
    Division of Nephrology, Tufts Medical Center, Boston, MA, USA
    Nephrol Dial Transplant 27:647-56. 2012
    ..Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance...
  7. pmc Evaluation of the gene-age interactions in HDL cholesterol, LDL cholesterol, and triglyceride levels: the impact of the SORT1 polymorphism on LDL cholesterol levels is age dependent
    Brian H Shirts
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
    Atherosclerosis 217:139-41. 2011
    ..These findings may help elucidate the mode of action of the SORT1 gene and impact potential therapeutic interventions targeting this pathway...
  8. doi Effects of ethanol intake on lipoproteins and atherosclerosis
    Eliot A Brinton
    Department of Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA
    Curr Opin Lipidol 21:346-51. 2010
    ..This article reviews published studies regarding effects of ethanol intake on lipoprotein levels and function as they relate to atherosclerosis, with special emphasis on recent publications in the past 2 years...
  9. pmc Genetic architecture of complex traits predisposing to nephropathy: hypertension
    Steven C Hunt
    Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84108, USA
    Semin Nephrol 30:150-63. 2010
    ..A brief review is provided of some key genes found to be associated with hypertension, including the genes identified from the nine genome-wide association studies published to date...
  10. doi Two-dimensional, sex-specific autosomal linkage scan of the number of sodium pump sites
    Sandra J Hasstedt
    Department of Human Genetics, University of Utah School of Medicine, University of Utah, Salt Lake City, Utah 84112, USA
    J Hypertens 28:740-7. 2010
    ..Obesity, hypertension, and diabetes associate with the activity of the sodium pump, motivating gene discovery for sodium pump number...
  11. pmc Altered composition of triglyceride-rich lipoproteins and coronary artery disease in a large case-control study
    Paul N Hopkins
    Cardiovascular Genetics Research, Department of Internal Medicine, Cardiology Division, University of Utah School of Medicine, Salt Lake City, UT 84108, USA
    Atherosclerosis 207:559-66. 2009
    ..30 with TG>150mg/dL) indicative of atherogenic remnant accumulation (type III hyperlipidemia). However, virtually no reports are available which examine potential associations between CAD and VLDL-C/TG at the lower end of the spectrum...
  12. pmc Serum bilirubin levels, UGT1A1 polymorphisms and risk for coronary artery disease
    Arno Lingenhel
    Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schopfstrasse 41, A 6020 Innsbruck, Austria
    Exp Gerontol 43:1102-7. 2008
    ..1mg/dl increase of bilirubin. These results indicate that it is rather decreased bilirubin levels in general than the changes in the genetic variation of this gene that increase the risk for CAD...
  13. ncbi Sodium bicarbonate cotransporter polymorphisms are associated with baseline and 10-year follow-up blood pressures
    Steven C Hunt
    Cardiovascular Genetics Division, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA
    Hypertension 47:532-6. 2006
    ..These results additionally confirm the involvement of SLC4A5 with blood pressure control, although the mechanism is still unclear...
  14. ncbi Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides
    Hilary Coon
    Neurodevelopmental Genetics Project, Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA
    Hum Genet 117:444-51. 2005
    ..This study replicates the involvement of USF1 in FCHL and related lipid traits in a family sample not ascertained for FCHL...