Bone density varies between races and by gender. Blacks and men tend to have higher bone densities than whites and women. Lately, estrogen metabolism has slowly gained recognition as an important determinant of bone density in postmenopausal women. Because recent reports suggest that estrogen is likewise important to skeletal health in men as it is in women, we believe that estrogen metabolism also plays a critical role in bone loss and bone maintenance in men. We propose that differences in estrogen metabolism may account for gender and racial differences in bone density. Furthermore, we hypothesize that this variability in estrogen metabolism is due to CYP gene polymorphisms of the key enzymes that metabolize estrogen resulting in variants that have altered enzyme activity affecting the balance between inactive and active estrogen metabolites. To date there is very limited proof, mostly in-vitro, that these variants have altered catalytic function. This proposal would serve to fill in this gap in knowledge and establish the biological significance of CYP gene polymorphism on enzyme activity and bone density in the elderly. The primary aims of this proposal are 1) to determine the prevalence of gene polymorphism of CYP1A1, CYP1B1, CYP1A2 and CYP3A4 among women and men of different ethnic groups 2) to determine the functional correlates of polymorphisms of the above-mentioned genes on estrogen status and bone density. This is a cross-sectional study of postmenopausal women and men 50 years of age or over, the population who are at highest risk for bone loss and osteoporosis. We intend to establish the CYP genotypes that are over-represented in a particular population and evaluate the functional status of the different variants by measuring urinary estrogen metabolites. Although it is not considered a primary goal, we will also measure bone mineral density and test the hypothsesis that variants that preferentially shifts estrogen metabolism to the inactive pathway is associated with a lower bone density and vice -versa. These data will be used to develop a full proposal and test the long-term hypothesis that CYP 450 enzyme gene polymorphism is important for bone mass maintenance and bone loss in elderly men and women. Another long-term goal is to extend evaluation to the younger population, to determine if polymorphisms of the CYP genes are important determinant of peak bone mass.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR049401-03
Application #
6711807
Study Section
Special Emphasis Panel (ZAR1-RJB-A (O3))
Program Officer
Mcgowan, Joan A
Project Start
2003-03-01
Project End
2006-02-28
Budget Start
2004-02-29
Budget End
2005-02-28
Support Year
3
Fiscal Year
2004
Total Cost
$74,750
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Napoli, Nicola; Vattikuti, Swapna; Yarramaneni, Jayasree et al. (2012) Increased 2-hydroxylation of estrogen is associated with lower body fat and increased lean body mass in postmenopausal women. Maturitas 72:66-71
Napoli, Nicola; Vattikuti, Swapna; Ma, Cynthia et al. (2010) High prevalence of low vitamin D and musculoskeletal complaints in women with breast cancer. Breast J 16:609-16
Napoli, Nicola; Rini, Giovam Battista; Serber, Daniel et al. (2009) The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density. Bone 44:442-8
Napoli, Nicola; Varadharajan, Ana; Rini, Giovam Batista et al. (2009) Effects of polymorphisms of the sex hormone-binding globulin (SHBG) gene on free estradiol and bone mineral density. Bone 45:1169-74
Napoli, Nicola; Thompson, Jennifer; Civitelli, Roberto et al. (2007) Effects of dietary calcium compared with calcium supplements on estrogen metabolism and bone mineral density. Am J Clin Nutr 85:1428-33
Napoli, Nicola; Armamento-Villareal, Reina (2007) Estrogen hydroxylation in osteoporosis. Adv Clin Chem 43:211-27
Napoli, N; Faccio, R; Shrestha, V et al. (2007) Estrogen metabolism modulates bone density in men. Calcif Tissue Int 80:227-32
Napoli, Nicola; Donepudi, Sirisha; Sheikh, Sharmin et al. (2005) Increased 2-hydroxylation of estrogen in women with a family history of osteoporosis. J Clin Endocrinol Metab 90:2035-41
Napoli, Nicola; Villareal, Dennis T; Mumm, Steven et al. (2005) Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. J Bone Miner Res 20:232-9
Armamento-Villareal, Reina C; Napoli, Nicola; Klug, Thomas et al. (2004) The oxidative metabolism of estrogen modulates response to ERT/HRT in postmenopausal women. Bone 35:682-8