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The overall research focus of the genetic epidemiological group is on the genetics of osteoporosis and related conditions. Multiple studies have documented osteoporotic fracture and its risk factors to be under substantial genetic control with 50 percent to 70 percent heritability (Ioannidis et al., 2007, Demissie 2007)
To this end, we perform statistical genetic analyses of bone mass and bone geometry using data from the well-known Framingham Heart Study (FHS) cohorts. We were among the first groups to report a gender-specific heritability of osteoporosis (Karasik et al., 2003), as well as to identify several novel candidate genes, such as estrogen receptor ß (Shearman et al., 2004), methylenetetrahydrofolate reductase (McLean et al., 2004), interleukin-6 (Ferrari et al., 2004), endothelial nitric oxide synthase (Cho et al., 2008), and recently, peroxisome proliferator activated receptor (Ackert-Bicknell et al., 2008). We are studying novel phenotypes, such as a bone age score (Karasik et al., 2004) and geometric properties of hip (Demissie et al., 2007) and hand bones (Karasik et al., 2008).
Our most cutting-edge work involves the performance of genome-wide association analyses (GWAS)(Kiel et al., 2007, Lunetta et al., 2007), using novel data from the Framingham SNP Health Association Resource (SHARe). The GWAS meta-analyses require large consortia of genetic epidemiological studies; therefore, we actively participate in several such international collaborations, such as the GEFOS/GENOMOS (Ioannidis et al., 2007, van Meurs et al., 2008) and CHARGE (http://depts.washington.edu/chargeco/wiki/Main_Page ) consortia.
Our search for genes suggested by the GWAS and linkage studies in humans is reinforced by a parallel search in mouse syntenic regions, based on homology between the species (via ongoing collaboration with the colleagues from the Jackson Laboratories). It is expected that differences between the mouse sublines in bone mass, geometry and bone quality are reflected in differentially expressed genes, as well as in genome sequence differences between the mouse strains. This would allow us to expedite the identification of new gene candidates, associated in our human sample, in parallel with functional experiments in mouse models.
ACKERT-BICKNELL, C. L., DEMISSIE, S., MARIN DE EVSIKOVA, C., HSU, Y. H., DEMAMBRO, V. E., KARASIK, D., CUPPLES, L. A., ORDOVAS, J. M., TUCKER, K. L., CHO, K., CANALIS, E., PAIGEN, B., CHURCHILL, G. A., FOREJT, J., BEAMER, W. G., FERRARI, S., BOUXSEIN, M. L., KIEL, D. P. & ROSEN, C. J. (2008) PPARG by dietary fat interaction influences bone mass in mice and humans. J Bone Miner Res, 23, 1398-408.
CHO, K., DEMISSIE, S., DUPUIS, J., CUPPLES, L. A., KATHIRESAN, S., BECK, T. J., KARASIK, D. & KIEL, D. P. (2008) Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans. Bone, 42, 53-60.
DEMISSIE, S., DUPUIS, J., CUPPLES, L. A., BECK, T. J., KIEL, D. P. & KARASIK, D. (2007) Proximal hip geometry is linked to several chromosomal regions: Genome-wide linkage results from the Framingham Osteoporosis Study. Bone, 40, 743-50.
FERRARI, S. L., KARASIK, D., LIU, J., KARAMOHAMED, S., HERBERT, A. G., CUPPLES, L. A. & KIEL, D. P. (2004) Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the framingham osteoporosis study. J Bone Miner Res, 19, 552-9.
IOANNIDIS, J. P., NG, M. Y., SHAM, P. C., ZINTZARAS, E., LEWIS, C. M., DENG, H. W., ECONS, M. J., KARASIK, D., DEVOTO, M., KAMMERER, C. M., SPECTOR, T., ANDREW, T., CUPPLES, L. A., DUNCAN, E. L., FOROUD, T., KIEL, D. P., KOLLER, D., LANGDAHL, B., MITCHELL, B. D., PEACOCK, M., RECKER, R., SHEN, H., SOL-CHURCH, K., SPOTILA, L. D., UITTERLINDEN, A. G., WILSON, S. G., KUNG, A. W. & RALSTON, S. H. (2007) Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res, 22, 173-83.
KARASIK, D., CUPPLES, L. A., HANNAN, M. T. & KIEL, D. P. (2003) Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham study. Bone, 33, 308-16.
KARASIK, D., HANNAN, M. T., CUPPLES, L. A., FELSON, D. T. & KIEL, D. P. (2004) Genetic contribution to biological aging: the Framingham Study. J Gerontol A Biol Sci Med Sci, 59, 218-26.
KARASIK, D., MYERS, R. H., CUPPLES, L. A., HANNAN, M. T., GAGNON, D. R., HERBERT, A. & KIEL, D. P. (2002a) Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study. J Bone Miner Res, 17, 1718-27.
KARASIK, D., MYERS, R. H., HANNAN, M. T., GAGNON, D., MCLEAN, R. R., CUPPLES, L. A. & KIEL, D. P. (2002b) Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis. Osteoporos Int, 13, 796-802.
KARASIK, D., SHIMABUKU, N. A., ZHOU, Y., ZHANG, Y., CUPPLES, L. A., KIEL, D. P. & DEMISSIE, S. (2008) A genome wide linkage scan of metacarpal size and geometry in the Framingham Study. Am J Hum Biol.
KIEL, D. P., DEMISSIE, S., DUPUIS, J., LUNETTA, K. L., MURABITO, J. M. & KARASIK, D. (2007) Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet, 8 Suppl 1, S14.
LUNETTA, K. L., D'AGOSTINO, R. B., SR., KARASIK, D., BENJAMIN, E. J., GUO, C. Y., GOVINDARAJU, R., KIEL, D. P., KELLY-HAYES, M., MASSARO, J. M., PENCINA, M. J., SESHADRI, S. & MURABITO, J. M. (2007) Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Med Genet, 8 Suppl 1, S13.
MCLEAN, R. R., KARASIK, D., SELHUB, J., TUCKER, K. L., ORDOVAS, J. M., RUSSO, G. T., CUPPLES, L. A., JACQUES, P. F. & KIEL, D. P. (2004) Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status. J Bone Miner Res, 19, 410-8.
SHEARMAN, A. M., KARASIK, D., GRUENTHAL, K. M., DEMISSIE, S., CUPPLES, L. A., HOUSMAN, D. E. & KIEL, D. P. (2004) Estrogen receptor Beta polymorphisms are associated with bone mass in women and men: the Framingham study. J Bone Miner Res, 19, 773-81.
VAN MEURS, J. B., TRIKALINOS, T. A., RALSTON, S. H., BALCELLS, S., BRANDI, M. L., BRIXEN, K., KIEL, D. P., LANGDAHL, B. L., LIPS, P., LJUNGGREN, O., LORENC, R., OBERMAYER-PIETSCH, B., OHLSSON, C., PETTERSSON, U., REID, D. M., ROUSSEAU, F., SCOLLEN, S., VAN HUL, W., AGUEDA, L., AKESSON, K., BENEVOLENSKAYA, L. I., FERRARI, S. L., HALLMANS, G., HOFMAN, A., HUSTED, L. B., KRUK, M., KAPTOGE, S., KARASIK, D., KARLSSON, M. K., LORENTZON, M., MASI, L., MCGUIGAN, F. E., MELLSTROM, D., MOSEKILDE, L., NOGUES, X., POLS, H. A., REEVE, J., RENNER, W., RIVADENEIRA, F., VAN SCHOOR, N. M., WEBER, K., IOANNIDIS, J. P. & UITTERLINDEN, A. G. (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. Jama, 299, 1277-90.
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