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Genetic Epidemiology of Longitudinal Change in Bone Mineral Density in Mexican Americans: The San Antonio Family Osteoporosis Study

Shaffer, John R (2008) Genetic Epidemiology of Longitudinal Change in Bone Mineral Density in Mexican Americans: The San Antonio Family Osteoporosis Study. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Motivation: Bone mineral density (BMD), the principal determinant of bone strength and a risk factor for osteoporosis, is the net result of two processes: (i) the acquisition of peak BMD during young adulthood, and (ii) the subsequent rate of bone loss with age. While the genetics of peak BMD has been extensively studied, the specific genetic polymorphisms influencing peak BMD and the genetic contribution to bone loss are largely unknown. We investigated the extent to which genes influence 5-year change in BMD and searched for specific chromosomal regions influencing peak BMD and change in BMD in 1047 Mexican Americans from 34 large, multigenerational families. Methods: BMD measurements of the hip, spine, and forearm were collected at baseline and follow-up (3-8 years later, mean = 5.6 years) by dual-energy x-ray absoptiometry, from which annual BMD change was calculated. Pedigree-based maximum likelihood methods modeling the variance decomposition of longitudinal and cross-sectional measurements of BMD were used to estimate heritability (h²) and perform genome-wide linkage analysis (using a 7.6 cM genetic map) for BMD change and peak BMD. The effects of several environmental covariates, notably sex, age, weight, change in weight, and menopause, were simultaneously modeled.Results: We determined that change in BMD varied over time and could be categorized into two heritable (h² = 31% to 44%) phases: early adult bone loss in participants <45 years of age and later bone loss in participants >45 years of age. A quantitative trait locus (QTL) influencing early bone loss was observed on chromosome 1q (LOD = 3.6) in the cohort <45 years; no specific chromosomal regions influencing change in BMD were observed in the cohort >45 years. By comparing cross-sectional genetic analyses at baseline and follow-up, we identified QTLs on chromosomes 6q and 13q with consistent effects on peak BMD of the hip and showed that QTLs influencing peak BMD did not overlap with QTLs influencing bone loss.Public health significance: This work demonstrated the importance of genes in the etiology of osteoporosis, a growing public health problem. Understanding the genetic determinants of bone strength could lead to new biological targets for the treatment of osteoporosis, and/or the identification of persons at risk who would benefit from preventative interventions.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shaffer, John Rjrs51@pitt.eduJRS51
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKammerer, Candace Mcmk3@pitt.eduCMK3
Committee MemberMitchell, Braxton Dbmitchel@medicine.umaryland.edu
Committee MemberWeeks, Daniel Eweeks@pitt.eduWEEKS
Committee MemberFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberZmuda, Joseph Mzmudaj@edc.pitt.eduEPIDJMZ
Committee MemberFerrell, Robert Erferrell@pitt.eduRFERRELL
Date: 23 June 2008
Date Type: Completion
Defense Date: 31 March 2008
Approval Date: 23 June 2008
Submission Date: 10 April 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 156
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: bone; bone loss; bone mineral density; heritability; linkage; osteoporosis; quantitative trait locus
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04102008-232707/, etd-04102008-232707
Date Deposited: 10 Nov 2011 19:35
Last Modified: 15 Nov 2016 13:39
URI: http://d-scholarship.pitt.edu/id/eprint/6970

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