A Polymorphic CYP19 TTTA Repeat Influences Aromatase Activity and Estrogen Levels in Elderly Men: Effects on Bone Metabolism Export

@article{citeulike:2083646, abstract = {Current evidence suggests that estrogen plays a dominant role in determining bone mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19 gene have been associated with low bone mass in young males. We previously reported an association between a TTTA repeat polymorphism in intron 4 of the CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the role of this polymorphism as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally for 2 (n = 300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight, nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal distribution of alleles, with two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele. Men with a high-repeat genotype (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low-repeat genotype (<nine repeats). The association with BMD was not significant in the subgroup of patients with high body mass index (>25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Moreover, the high-repeat genotype was less represented, although not significantly, in the vertebral fracture group with respect to the nonvertebral fracture group. Functional in vitro analysis after incubation with [3H]-androstenedione showed a higher aromatase activity in fibroblasts from subjects with a high-repeat genotype than in fibroblasts from subjects with a low-repeat genotype. In conclusion, differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk. 10.1210/jc.2003-031342}, author = {Gennari, Luigi and Masi, Laura and Merlotti, Daniela and Picariello, Lucia and Falchetti, Alberto and Tanini, Annalisa and Mavilia, Carmelo and Del Monte, Francesca and Gonnelli, Stefano and Lucani, Barbara and Gennari, Carlo and Brandi, Maria L.}, citeulike-article-id = {2083646}, citeulike-linkout-0 = {http://dx.doi.org/10.1210/jc.2003-031342}, citeulike-linkout-1 = {http://jcem.endojournals.org/content/89/6/2803#R19.abstract}, citeulike-linkout-2 = {http://jcem.endojournals.org/content/89/6/2803#R19.full.pdf}, citeulike-linkout-3 = {http://jcem.endojournals.org/cgi/content/abstract/89/6/2803}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/15181061}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=15181061}, day = {1}, doi = {10.1210/jc.2003-031342}, journal = {J Clin Endocrinol Metab}, keywords = {aromatase, gene, human, polymorphisms}, month = {June}, number = {6}, pages = {2803--2810}, posted-at = {2009-11-07 09:20:06}, priority = {2}, title = {A Polymorphic CYP19 TTTA Repeat Influences Aromatase Activity and Estrogen Levels in Elderly Men: Effects on Bone Metabolism}, url = {http://dx.doi.org/10.1210/jc.2003-031342}, volume = {89}, year = {2004} }

TY - JOUR ID - citeulike:2083646 L3 - citeulike-article-id:2083646 N2 - Current evidence suggests that estrogen plays a dominant role in determining bone mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19 gene have been associated with low bone mass in young males. We previously reported an association between a TTTA repeat polymorphism in intron 4 of the CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the role of this polymorphism as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally for 2 (n = 300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight, nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal distribution of alleles, with two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele. Men with a high-repeat genotype (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low-repeat genotype (<nine repeats). The association with BMD was not significant in the subgroup of patients with high body mass index (>25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Moreover, the high-repeat genotype was less represented, although not significantly, in the vertebral fracture group with respect to the nonvertebral fracture group. Functional in vitro analysis after incubation with [3H]-androstenedione showed a higher aromatase activity in fibroblasts from subjects with a high-repeat genotype than in fibroblasts from subjects with a low-repeat genotype. In conclusion, differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk. 10.1210/jc.2003-031342 IS - 6 JF - J Clin Endocrinol Metab EP - 2810 TI - A Polymorphic CYP19 TTTA Repeat Influences Aromatase Activity and Estrogen Levels in Elderly Men: Effects on Bone Metabolism VL - 89 SP - 2803 KW - aromatase KW - gene KW - human KW - polymorphisms AU - Gennari, Luigi AU - Masi, Laura AU - Merlotti, Daniela AU - Picariello, Lucia AU - Falchetti, Alberto AU - Tanini, Annalisa AU - Mavilia, Carmelo AU - Del Monte, Francesca AU - Gonnelli, Stefano AU - Lucani, Barbara AU - Gennari, Carlo AU - Brandi, Maria PY - 2004/06/01/ UR - http://dx.doi.org/10.1210/jc.2003-031342 ER -