465 J. Endocrinol. Invest. 30: 465-469, 2007 Key-words: Genetics, peak bone mass, aromatase, CYP19, TTTA polymor- phism. Correspondence: D. Kastelan, MD, PhD, Division of Endocrinology, De- partment of Internal Medicine, University Hospital Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia. E-mail: dkastelan@inet.hr Accepted December 12, 2006. Decreased peak bone mass is associated with a 3-bp deletion/insertion of the CYP19 intron 4 polymorphism: Preliminary data from the GOOS study D. Kastelan 1 , Z. Grubic 2 , I. Kraljevic 1 , K. Duric 3 , I. Kardum 1 , T. Dusek 1 , K. Stingl 2 , Z. Giljevic 1 , V. Kerhin-Brkljacic 2 , E. Suchanek 3 , and M. Korsic 1 1 Division of Endocrinology, Department of Internal Medicine; 2 Tissue Typing Centre; 3 Department of Obstetrics and Gynecology, University Hospital Zagreb, Zagreb, Croatia ABSTRACT. Finding that estrogen plays an impor- tant role in bone homeostasis in men prompted research on relationship of polymorphism at the CYP19 gene and the bone mass. Therefore, influ- ence of 3-bp deletion/insertion polymorphism of CYP19 (TTTA) 7 allele on the peak bone mass at- tainment in males was studied. Fifty-eight unrelat- ed male participants, aged 21-35, were selected depending on the presence of (TTTA) 7 (no.=19) or (TTTA) 7-3 (no.=39) alleles from the initial cohort of 92 young males. Heterozygotes (TTTA) 7 /(TTTA) 7-3 (no.=13) were not included in the analysis. Serum levels of estradiol, free testosterone, 25-hydroxy- vitamin D, bone alkaline phosphatase, osteocal- cin, and -crosslaps were measured. Bone mass was measured by DXA at the hip and at the spine. (TTTA) 7-3 allele was associated with significantly lower femoral neck bone mineral density (BMD) (p=0.02). Logistic regression model indicated strong association of (TTTA) 7-3 allele with low BMD in the range of osteopenia/osteoporosis (p=0.014, odds ratio 12.36, confidence intervals 1.65-92.46). In the present study association of 3-bp deletion polymorphism of the (TTTA) 7 allele with decreased peak bone mass in males is report- ed for the first time. However, further studies are necessary to elucidate the functional relevance of this polymorphism. (J. Endocrinol. Invest. 30: 465-469, 2007) © 2007, Editrice Kurtis INTRODUCTION Osteoporosis is a skeletal disease characterized by increased risk of low trauma fracture. Fracture risk, at any age, depends on the attained peak bone mass in youth and the rate of bone loss during ageing. Thus, any condition that reduces peak bone mass increas- es the probability of developing osteoporosis. Hereditary factors have a great impact on bone mass and they account for 50-80% of its variance (1). The magnitude of genetic effect is higher in the young than in the elderly (2). Numerous association studies tried to identify genes responsible for osteoporosis (3-7). However, most of them have been performed in women, and those which investigate genes in- volved in pathogenesis of osteoporosis in men re- cruited mostly middle-aged or elderly men, with the exception of the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (8). Aromatase, the product of CYP19 gene, is an en- zyme responsible for synthesis of estrogen from an- drogenic precursors. As the polymorphism of CYP19 gene is related to differences in estrogen synthesis, it could also influence the risk of estrogen-depend- ent diseases. Indeed, several studies confirm the as- sociation of CYP19 polymorphism with breast and prostate malignancies (9-11). It is well known that changes in estrogen concen- tration affect bone metabolism in women. However, several lines of evidence suggest that estrogen, rath- er than testosterone, is more closely related to bone mineral density (BMD) in men, too. Reports of male patients with low bone mass and unfused epiphy- ses due to estrogen receptor mutation or aromatase deficiency have shown the importance of estrogen in bone homeostasis in males (12, 13). Moreover, a few studies demonstrate greater impact of estrogen