Abstract
This paper reports the results of a series of univariate and bivariate statistical genetic analyses that were performed on a sample of nuclear and more complex pedigrees (N = 567 individuals) of an ethnically homogenous White population. Our major objectives were: (1) To quantitatively evaluate the extent and pattern of the putative genetic effects on plasma level variation and covariation of the intact parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D]; (2) To evaluate the extent of the possible genetic covariation between each of the two calciotropic hormones and two important bone mass traits, namely radiographic hands bone mineral density (BMD) and cortical index (CI). Variance component analysis, as implemented in the statistical package FISHER unambigously demonstrated that in addition to age, genetic factors contribute significantly to interindividual variation of both calciotropic hormones (37.5% for PTH and 53.3% for 25(OH)D). Complex segregation analysis strongly suggested the involvement of major gene effects into the determination of 25(OH)D levels, but was not clear cut with respect to PTH. Significant correlations between circulating levels of study hormones were found (−0.146, P < 0.05 in men and −0.194, P < 0.01 in women). However, no genetic correlation was revealed between PTH and 25(OH)D plasma concentrations. Bivariate analyses showed that familial cross correlations between PTH and BMD and CI measured at the bones of the hand were consistently statistically significant, suggesting moderate, but detectable pleiotropic genetic effects. The corresponding genetic correlations were −0.461 ± 0.153 and −0.223 ± 0.113, respectively. Circulating levels of 25(OH)D showed neither phenotypic nor genetic correlation with any of the BMD or CI variation.
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Aguado, P., del Campo, M. T., Garces, M. V., Gonzalez-Casaus, M. L., Bernad, M., Gijon-Banos, J., Mola, E. M., Torrijos, A., & Martinez, M. E. (2000). Low vitamin D levels in outpatient postmenopausal women from a rheumatology clinic in Madrid, Spain: Their relationship with bone mineral density. Osteoporos. Int. 11:739–744.
Boehnke, M., Moll, P. P., Lange, K., Weidman, W. H., & Kottke, B. A. (1986). Univariate and bivariate analyses of cholesterol and triglyceride levels in pedigrees. Am. J. Med. Genet. 23:775–792.
Bonofiglio, D., Maggiolini, M., Catalano, S., Marsico, S., Aquila, S., & Ando, S. (2001). Bone mineral density is inversely related to parathyroid hormone in adolescent girls. Horm. Metabol. Res. 33:170–174.
Carmeliet, G., Verstuyf, A., Daci, E., & Bouillon, R. (1999). The Vitamin D hormone and its nuclear receptor: Genomic Mechanisms involved in bone biology. In Seibel, M. J., Robins, S. P., & Bilezikian, J. P. (eds.), Dynamics of Bone and Cartilage Metabolism, Academic Press, New York, pp. 217–231.
Center, J. R., Nguyen, T. V., Sambrook, P. N., & Eisman, J. A. (1999). Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J. Clin. Endocrinol. Metabol. 84:3626–3635.
Dawson-Hughes, B., Harris, S. S., & Dallal, G. E. (1997). Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am. J. Clin. Nutr. 65:67–71.
Elston, R. C. (1981). Segregation analysis. Adv. Hum. Genet. 11:63–120.
Falconer, D. S., & Mackay, T. F. C. (1996). Introduction to Quantitative Genetics, Longman, England.
Fitzpatrick, L. A., & Bilezikian, J. P. (1999). Parathyroid hormone: Structure, function and dynamic actions. In Seibel, M. J., Robins, S. P., & Bilezikian, J. P. (eds.), Dynamics of Bone and Cartilage Metabolism, Academic Press, New York, pp. 187–202.
Fradinger, E. E., & Zanchetta, J. R. (2001). Vitamin D and bone mineral density in ambulatory women living in Buenos Aires, Argentina. Osteoporos. Int. 12:24–27.
Garnero, P., Arden, N. K., Griffiths, G., Delmas, P. D., & Spector, T. D. (1996). Genetic influence on bone turnover in postmenopausal twins. J. Clin. Endocrinol. Metabol. 81:140–146.
Ginsburg, E. (1997). Program Package for Mendelian analysis of pedigree data (MAN) Version 5. Tel Aviv, Israel. Tech Rep Tel Aviv University Medical Faculty.
Ginsburg, E., & Livshits, G. (1999). Segregation analysis of quantitative traits. A review. Ann. Hum. Biol. 26:103–129.
Gong, G., Johnson, M. L., Barger-Lux, M. J., & Heaney, R. P. (1999). Association of bone dimensions with a parathyroid hormone gene polymorphism in women. Osteoporos. Int. 9:307–311.
Guo, S. W., & Lange, K. (2000). Genetic mapping of complex traits: Promise, problems, and prospects. Theor. Popul. Biol. 57:1–11.
Harrela, M., Koistinen, H., Kaprio, J., Lejtovirta, M., Tuomilehto, J., Eriksson, J., Toivanen, L., Kosenvuo, M., Leinonen, R., Koistinen, R., & Seppala, M. (1996). Genetic and environmental components of interindividual variation in circulating levels of IGF-1, IGF-II, IGFPB-1, and IGFBP-3. J. Clin. Invest. 98:2612–2615.
Harris, M., Nguyen, T. V., Howard, G. M., Kelly, P. J., & Eisman, J. A. (1998). Genetic and environmental correlations between bone formation and bone mineral density: A twin study. Bone 22:141–145.
Hosoi, T., Miyao, M., Inoue, S., Hoshino, S., Shiraki, M., Orimo, H., & Ouchi, Y. (1999). Association study of parathyroid hormone gene polymorphism and bone mineral density in Japanese postmenopausal women. Calif. Tissue Int. 64:205–208.
Hunter, D., DeLange, M., Snieder, H., MacGregor, A. J., Swaminathan, R., Thakker, R. V., & Spector, T. D. (2001). Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation. J. Bone Miner. Res. 16:371–378.
Johnson, G. C. L., & Todd, J. A. (2000). Strategies in complex disease mapping. Curr. Opin. Genet. Dev. 110:330–334.
Kalichman, L., Cohen, Z., Kobyliansky, E., & Livshits, G. (2002). Interrelationship between bone aging traits and main anthropological characteristics. Am. J. Hum. Biol. 14:380–390.
Karasik, D., Kobyliansky, E., & Livshits, G. (2000a). Ethnic and genetic factors in bone aging. In Siniarska, A., & Walanska, N. (eds.), Ecology of Aging, Kamla-Raj Enterprises, Delhi, India, pp. 167–190.
Karasik, D., Ginsburg, E., Livshits, G., Pavlovsky, O., & Kobyliansky, E. (2000b). Evidence of major gene control of cortical bone loss in humans. Genet. Epidem. 19:410–421.
Kelly, P. J., Morrison, N. A., Sambrook, P. N., Nguyen, T. V., & Eisman, J. A. (1995). Genetic influences on bone turnover, bone density and fracture. Eur. J. Endocrinol. 133:265–271.
Khosla, S. (2002). Androgens and androgenic progestins. In Marcus, R., Feldman, D., & Kesley, J. (eds.), Osteoporosis, Academic Press, San Diego, Chap. 76, CA, p. 709–724.
Kleerekoper, M., Nelson, D. A., Peterson, E. L., Flynn, M. J., Pawluszka, A. S., Jacobsen, G., & Wilson, P. (1994). Reference data for bone mass, calciotropic hormones and biochemical markers of bone remodeling in older (55–75). Postmenopausal white and black women. J. Bone Miner Res. 9:1267–1276.
Lange, K., Boehnke, M., & Weeks, D. (1998). Program for pedigree analysis: Mendel, Fisher, Gene. Genet Epidem. 5:471–472.
Lips, P., Duong, T., Oleksik, A., Black, D., Cummings, S., Cox, D., & Nickelsen, T. (2001). A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: Baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J. Clin. Endocrinol. Metabol. 86:1212–1221.
Livshits, G., Vainder, M., Graff, E., Blettner, M., Schettler, G., & Brunner, D. (1997). Tel-Aviv Heidelberg-Three-Generation offspring study: Genetic and environmental sources of plasma lipids, lipoproteins and apolipoproteins variation and covariation. Am. J. Hum. Biol. 9:357–370.
Livshits, G., Karasik, D., & Seibel, M. J. (1999a). Statistical genetic analysis of plasma levels of vitamin D: Familial study. Ann. Hum. Genet. 3:429–439.
Livshits, G., Karasik, D., Pavlovsky, O., & Kobyliansky, E. (1999b). Segregation analysis reveals a major gene effect in compact and cancellous bone mineral density in 2 populations. Hum. Biol. 71:155–72.
Livshits, G., Yakovenko, K., & Kobyliansky, E. (2000). Quantitative genetic analysis of circulating levels of biochemical markers of bone formation. Am. J. Med. Genet. 94:324–331.
Livshits, G., Karasik, D., & Kobyliansky, E. (2002). Complex segregation analysis of the phalanges and their age related changes. J. Bone Miner. Res. 17:1–10.
Manolagas, S. C. (2000). Birth and death of bone cells: Basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21:115–137.
Nakamura, K., Nashimoto, M., Hori, Y., & Yamamoto, M. (2000). Serum parathyroid hormone in healthy Japanese women in relation to serum 25–hydroxyvitamin D. Int. J. Vitam. Nutr. Res. 70:287–292.
Otremski, I., Karasik, D., & Livshits, G. (2000). Genetic variation and covariation of parathyroid hormone levels and bone density in human populations. Calif. Tissue Int. 66:168–175.
Pantsulaia, I., Trofimov, S., Kobyliansky, E., & Livshits, G. (2002). Pedigree based quantitative genetic analysis of interindividual variation in circulating levels of IGFBP-3. J. Bone Miner. Metab. 20:156–163.
Pavlovsky, O., & Kobyliansky, E. (1999). Population Biology of Human Aging, Angelo Pontecorboli Editore, Publishing House, Firenze, Italy, pp. 1–152.
Plato, C. C., Fox, K. M., & Tobin, J. D. (1994). Skeletal changes in human aging. In Crews, D. E., & Garruto, R. M. (eds.), Biological Anthropology and Aging, Oxford University Press, New York, pp. 272–300.
Tischkov, V. A. (1994). People of Russia. Encyclopedia, Moscow, Great Russian Encyclopedia Publishing House. (in Russian).
Tokita, A., Kelly, P. J., Nguyen, T. V., Qi, J. C., Morrison, N. A., Risteli, L., Risteli, J., Sambrook, P. N., & Eisman, J. A. (1994). Genetic influences on type I collagen synthesis and degradation: Further evidence for genetic regulation of bone turnover. J. Clin. Endocrinol. Metabol. 78:1461–1465.
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Livshits, G., Yakovenko, C. & Seibel, M. Substantial Genetic Effects Involved in Determination of Circulating Levels of Calciotropic Hormones in Human Pedigrees. Biochem Genet 41, 269–289 (2003). https://doi.org/10.1023/B:BIGI.0000006029.01736.64
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DOI: https://doi.org/10.1023/B:BIGI.0000006029.01736.64