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Mexican-American Family Osteo Study (MXFOS)

Dr. Braxton Mitchell, P.I.  

Osteoporosis is a major cause of morbidity among older Americans. The San Antonio Family Osteoporosis Study (SAFOS) initiated in 1997 with the aim of identifying the determinants of bone mineral density (BMD) in large Mexican American families. A total of 897 subjects from 34 families were enrolled in the baseline phase of this study. Extensive genotypic information was made available on these subjects through their concurrent participation in a larger study, the San Antonio Family Heart Study (SAFHS), designed to identify the genetic determinants of atherosclerosis in these families.

To date, we have obtained several exciting results from the SAFOS. Foremost among these was the detection of very strong evidence for linkage of forearm BMD to a region on chromosome 4p (multipoint lod score = 4.3). We also observed associations of increased BMD with diabetes and of decreased BMD with carotid wall thickening, a subclinical measure of atherosclerosis in women aged 40 yr and older. This latter observation supports a growing body of evidence suggesting that osteoporosis and CVD share common etiologic determinants.

We propose in the second 5-year funding period to re-measure BMD to assess 5-yr change in BMD and to begin fine mapping of the putative quantitative trait locus affecting BMD on chromosome 4p. Repeat DXA scans are currently being obtained in conjunction with the ongoing re-examination of SAFHS subjects. We will estimate heritability of 5-yr changes in BMD and determine predictors of bone loss. We will utilize a positional candidate gene approach to pursue the major fine mapping aim. We will sequence coding and regulatory regions of 20 genes in the region of linkage to identify sequence variation and will then genotype all common variants in the full sample of SAFOS participants for association and haplotype analysis.  

Publications

(as of 22 November 2010)  

(As of June 2013)

  1. Zheng HF, Duncan EL, Yerges-Armstrong LM, et al.: Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm. J Med Genet 50:473-478, 2013.  
  2. Koller DL, Zheng HF, Karasik D, et al.: Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women. J Bone Miner Res 28:547-558, 2013.  
  3. Zheng HF, Tobias JH, Duncan E, et al.: WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet 8:e1002745, 2012.   PMC3390364
  4. Liu J, Hoppman N, O'Connell JR, et al.: A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density. J Bone Miner Res 27:331-341, 2012.   PMC3319695
  5. Liu CT, Estrada K, Yerges-Armstrong LM, et al.: Assessment of gene-by-sex interaction effect on bone mineral density. J Bone Miner Res 27:2051-2064, 2012.   PMC3447125
  6. Estrada K, Styrkarsdottir U, Evangelou E, et al.: Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491-501, 2012.   PMC3338864
  7. Mitchell BD, Yerges-Armstrong LM: The genetics of bone loss: challenges and prospects. J Clin Endocrinol Metab 96:1258-1268, 2011.   PMC3085199
  8. Shaffer JR, Kammerer CM, Dressen AS, et al.: Rate of bone loss is greater in young Mexican American men than women: the San Antonio Family Osteoporosis Study. Bone 47:49-54, 2010.   PMC2891113
  9. Hoppman N, McLenithan JC, McBride DJ, et al.: A common variant in fibroblast growth factor binding protein 1 (FGFBP1) is associated with bone mineral density and influences gene expression in vitro. Bone 47:272-280, 2010.   PMC2902654.
  10. Shaffer JR, Kammerer CM, Bruder JM, et al.: Quantitative trait locus on chromosome 1q influences bone loss in young Mexican American adults. Calcif Tissue Int 84:75-84, 2009.   PMC2680710
  11. Shaffer JR, Kammerer CM, Bruder JM, et al.: Genetic influences on bone loss in the San Antonio Family Osteoporosis study. Osteoporos  Int 19:1759-1767, 2008.   PMC2712667
  12. Shaffer JR, Kammerer CM, Rainwater DL, et al.: Decreased bone mineral density is correlated with increased subclinical atherosclerosis in older, but not younger, Mexican American women and men: the San Antonio Family Osteoporosis Study. Calcif Tiss Int 81:430-441, 2007.  
  13. Ioannidis JP, Ng MY, Sham PC, et al.: Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 22:173-183, 2007.  
  14. Kammerer CM, Dualan AA, Samollow PB, et al.: Bone mineral density, carotid artery intimal medial thickness, and the vitamin D receptor BsmI polymorphism in Mexican American women. Calcif Tissue Int 75:292-298, 2004.  
  15. Mitchell BD, Kammerer CM, Schneider JL, et al.: Genetic and environmental determinants of bone mineral density in Mexican Americans: results from the San Antonio Family Osteoporosis Study. Bone 33:839-846, 2003.  
  16. Kao WH, Kammerer CM, Schneider JL, et al.: Type 2 diabetes is associated with increased bone mineral density in Mexican-American women. Arch Med Res 34:399-406, 2003.  
  17. Kammerer CM, Schneider JL, Cole SA, et al.: Quantitative trait loci on chromosomes 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican Americans. J Bone Miner Res 18:2245-2252, 2003.  
  18. Mitchell BD, Cole SA, Bauer RL, et al.: Genes influencing variation in serum osteocalcin concentrations are linked to markers on chromosomes 16q and 20q. J Clin Endocrinol Metab 85:1362-1366, 2000.