Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

CYP19A1 polymorphisms are associated with bone mineral density in Chinese men

  • 135 Accesses

  • 11 Citations


Aromatase-dependent biosynthesis of estrogen plays an important role in maintenance of the male skeleton, and Cytochrome p450 aromatase is the key enzyme to catalyze the conversion of androgen precursors to estrogens. We investigated the association of polymorphisms in the CYP19A1 gene and bone mineral density in a Chinese cohort. 2392 extreme low femoral neck BMD cases or extreme high femoral neck BMD controls were selected from a population-based cohort and genotyped for eight SNPs in the CYP19A1 gene. Significant associations for rs17703883, rs12594287 and rs16964201 SNPs with BMD were found in men only. Men with TC/CC genotypes in the rs17703883 SNP had a 1.5 times higher risk of having extreme low femoral neck BMD (P = 0.003, empirical P value = 0.05), and decreased BMDs at total body (P = 0.004, empirical P value = 0.07) and total hip (P = 0.003, empirical P value = 0.05). Men carrying AA/AG genotypes in the rs12594287 SNP had a 30% reduced risk of having extreme low femoral neck BMD (P = 0.007, empirical P value = 0.12), and increased BMDs at total body (P = 0.0009, empirical P value = 0.018) and total hip (P = 0.001, empirical P value = 0.02). Men carrying TT/TC genotypes in the rs16964201 SNP had a 40% reduced risk of having extreme low femoral neck BMD (P = 0.005, empirical P value = 0.087), and increased BMDs at total body (P = 0.0001, empirical P value = 0.002) and total hip (P = 0.0006, empirical P value = 0.012). Haplotype analysis showed that the G-C-T-A-T haplotype was significantly related to higher BMD. Our finding suggests that genetic variations in the CYP19A1 gene are significantly associated with BMD at different skeletal sites in adult men, but not in women.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

  2. Bilezikian JP, Morishima A, Bell J, Grumbach MM (1998) Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603

  3. Bouillon R, Bex M, Vanderschueren D, Boonen S (2004) Estrogens are essential for male pubertal periosteal bone expansion. J Clin Endocrinol Metab 89:6025–6029

  4. Corbin CJ, Graham-Lorence S, McPhaul M, Mason JI, Mendelson CR, Simpson ER (1988) Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells. Proc Natl Acad Sci USA 85:8948–8952

  5. Dick IM, Devine A, Prince RL (2005) Association of an aromatase TTTA repeat polymorphism with circulating estrogen, bone structure, and biochemistry in older women. Am J Physiol Endocrinol Metab 288:E989–E995

  6. Enjuanes A, Garcia-Giralt N, Supervia A, Nogues X, Mellibovsky L, Carbonell J, Grinberg D, Balcells S, Diez-Perez A (2003) Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments. Eur J Endocrinol 148:519–526

  7. Enjuanes A, Garcia-Giralt N, Supervia A, Nogues X, Ruiz-Gaspa S, Bustamante M, Mellibovsky L, Grinberg D, Balcells S, Diez-Perez A (2006) A new SNP in a negative regulatory region of the CYP19A1 gene is associated with lumbar spine BMD in postmenopausal women. Bone 38:738–743

  8. Eriksen EF, Langdahl B, Vesterby A, Rungby J, Kassem M (1999) Hormone replacement therapy prevents osteoclastic hyperactivity: a histomorphometric study in early postmenopausal women. J Bone Miner Res 14:1217–1221

  9. Falahati-Nini A, Riggs BL, Atkinson EJ, O’Fallon WM, Eastell R, Khosla S (2000) Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106:1553–1560

  10. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

  11. Gennari L, Masi L, Merlotti D, Picariello L, Falchetti A, Tanini A, Mavilia C, Del Monte F, Gonnelli S, Lucani B, Gennari C, Brandi ML (2004) A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism. J Clin Endocrinol Metab 89:2803–2810

  12. Herrmann BL, Saller B, Janssen OE, Gocke P, Bockisch A, Sperling H, Mann K, Broecker M (2002) Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin Endocrinol Metab 87:5476–5484

  13. Hsu YH, Venners SA, Terwedow HA, Feng Y, Niu T, Li Z, Laird N, Brain JD, Cummings SR, Bouxsein ML, Rosen CJ, Xu X (2006) Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women. Am J Clin Nutr 83:146–154

  14. Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 2:1132–1136

  15. Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730

  16. Kristensen VN, Harada N, Yoshimura N, Haraldsen E, Lonning PE, Erikstein B, Karesen R, Kristensen T, Borresen-Dale AL (2000) Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 19:1329–1333

  17. Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS (2003) Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 88:204–210

  18. Lorentzon M, Swanson C, Eriksson AL, Mellstrom D, Ohlsson C (2006) Polymorphisms in the aromatase gene predict areal BMD as a result of affected cortical bone size: the GOOD study. J Bone Miner Res 21:332–339

  19. Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Adjei AA, Weinshilboum RM (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65:11071–11082

  20. Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M, Clyne CD, Davis S, Simpson ER, Carani C (2004) Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab 89:61–70

  21. Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137

  22. Masi L, Becherini L, Gennari L, Amedei A, Colli E, Falchetti A, Farci M, Silvestri S, Gonnelli S, Brandi ML (2001) Polymorphism of the aromatase gene in postmenopausal Italian women: distribution and correlation with bone mass and fracture risk. J Clin Endocrinol Metab 86:2263–2269

  23. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689–3698

  24. Oz OK, Zerwekh JE, Fisher C, Graves K, Nanu L, Millsaps R, Simpson ER (2000) Bone has a sexually dimorphic response to aromatase deficiency. J Bone Miner Res 15:507–514

  25. Oz OK, Hirasawa G, Lawson J, Nanu L, Constantinescu A, Antich PP, Mason RP, Tsyganov E, Parkey RW, Zerwekh JE, Simpson ER (2001) Bone phenotype of the aromatase deficient mouse. J Steroid Biochem Mol Biol 79:49–59

  26. Peng Z, Li X, Makela S, Vaananen HK, Poutanen M (2004) Skeletal changes in transgenic male mice expressing human cytochrome p450 aromatase. J Bone Miner Res 19:1320–1328

  27. Qin ZS, Niu T, Liu JS (2002) Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet 71:1242–1247

  28. Remes T, Vaisanen SB, Mahonen A, Huuskonen J, Kroger H, Jurvelin JS, Penttila IM, Rauramaa R (2003) Aerobic exercise and bone mineral density in middle-aged Finnish men: a controlled randomized trial with reference to androgen receptor, aromatase, and estrogen receptor alpha gene polymorphisms small star, filled. Bone 32:412–420

  29. Riancho JA, Zarrabeitia MT, Valero C, Sanudo C, Hernandez JL, Amado JA, Zarrabeitia A, Gonzalez-Macias J (2005) Aromatase gene and osteoporosis: relationship of ten polymorphic loci with bone mineral density. Bone 36:917–925

  30. Riggs BL, Khosla S, Melton LJ III (1998) A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 13:763–773

  31. Salmen T, Heikkinen AM, Mahonen A, Kroger H, Komulainen M, Pallonen H, Saarikoski S, Honkanen R, Maenpaa PH (2003) Relation of aromatase gene polymorphism and hormone replacement therapy to serum estradiol levels, bone mineral density, and fracture risk in early postmenopausal women. Ann Med 35:282–288

  32. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434

  33. Sebastian S, Bulun SE (2001) A highly complex organization of the regulatory region of the human CYP19 (aromatase) gene revealed by the Human Genome Project. J Clin Endocrinol Metab 86:4600–4602

  34. Somner J, McLellan S, Cheung J, Mak YT, Frost ML, Knapp KM, Wierzbicki AS, Wheeler M, Fogelman I, Ralston SH, Hampson GN (2004) Polymorphisms in the P450 c17 (17-hydroxylase/17,20-Lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women. J Clin Endocrinol Metab 89:344–351

  35. Szulc P, Claustrat B, Marchand F, Delmas PD (2003) Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study. J Clin Endocrinol Metab 88:5240–5247

  36. Taxel P, Kennedy DG, Fall PM, Willard AK, Clive JM, Raisz LG (2001) The effect of aromatase inhibition on sex steroids, gonadotropins, and markers of bone turnover in older men. J Clin Endocrinol Metab 86:2869–2874

  37. Tofteng CL, Kindmark A, Brandstrom H, Abrahamsen B, Petersen S, Stiger F, Stilgren LS, Jensen JE, Vestergaard P, Langdahl BL, Mosekilde L (2004) Polymorphisms in the CYP19 and AR genes—relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: the Danish Osteoporosis Prevention Study. Calcif Tissue Int 74:25–34

  38. Turner RT, Riggs BL, Spelsberg TC (1994) Skeletal effects of estrogen. Endocr Rev 15:275–300

  39. Valero C, Zarrabeitia MT, Hernandez JL, Zarrabeitia A, Gonzalez-Macias J, Riancho JA (2005) Bone mass in young adults: relationship with gender, weight and genetic factors. J Intern Med 258:554–562

  40. Van Pottelbergh I, Goemaere S, Kaufman JM (2003) Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab 88:3075–3081

  41. Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV, Verhoeven G, Vanderschueren D (2006) Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J Bone Miner Res 21:576–585

  42. Yang TL, Xiong DH, Guo Y, Recker RR, Deng HW (2006) Association analyses of CYP19 gene polymorphisms with height variation in a large sample of Caucasian nuclear families. Hum Genet 120:119–125

  43. Zarrabeitia A, Zarrabeitia MT, Valero C, Gonzalez-Macias J, Riancho JA (2004a) Age-related influence of common aromatase gene polymorphisms on bone mass of healthy men. Bone 35:243–248

  44. Zarrabeitia MT, Hernandez JL, Valero C, Zarrabeitia AL, Garcia-Unzueta M, Amado JA, Gonzalez-Macias J, Riancho JA (2004b) A common polymorphism in the 5′-untranslated region of the aromatase gene influences bone mass and fracture risk. Eur J Endocrinol 150:699–704

Download references


This study was supported by NIH grant R01 AR045651 and grants R01 HL073882. We would like to thank the local Bureaus of Health of Dongzhi and Wangjang in Anhui Province, China for their support.

Author information

Correspondence to Xiping Xu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hong, X., Hsu, Y., Terwedow, H. et al. CYP19A1 polymorphisms are associated with bone mineral density in Chinese men. Hum Genet 121, 491–500 (2007). https://doi.org/10.1007/s00439-006-0303-1

Download citation


  • Bone Mineral Density
  • Postmenopausal Woman
  • Femoral Neck Bone Mineral Density
  • CYP19A1 Gene
  • High Bone Mineral Density