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Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women.

ABSTRACT: CONTEXT:A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor beta gene (ESR2) is located. OBJECTIVE:The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation. DESIGN:This was a population-based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene. SETTING:The study was conducted at an academic research laboratory and medical center. PATIENTS AND OTHER PARTICIPANTS:A total of 411 healthy men (aged 18-61 yr) and 1291 healthy premenopausal women (aged 20-50 yr) living in Indiana participated in the study. INTERVENTION(S):There were no interventions. MAIN OUTCOME MEASURE(S):The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine. RESULTS:Significant association of spine BMD was found with three SNPs in men and one SNP in women (P < or = 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage. CONCLUSIONS:ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.

SUBMITTER: Ichikawa S

PROVIDER: S-EPMC1948071 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women.

Ichikawa Shoji S Koller Daniel L DL Peacock Munro M Johnson Michelle L ML Lai Dongbing D Hui Siu L SL Johnston C Conrad CC Foroud Tatiana M TM Econs Michael J MJ

The Journal of clinical endocrinology and metabolism 20050823 11

<h4>Context</h4>A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor beta gene (ESR2) is located.<h4>Objective</h4>The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation.<h4>Design</h4>This was a population-based genetic associa ...[more]

PMID: 16118344

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Project description:Genetic risk of low bone mineral density in women remains unclear. This study found that a large percentage of Caucasian women have a high genetic risk of osteoporosis, and genetic risk scores are significantly associated with BMD variation in a bone healthy sample of Caucasian women. INTRODUCTION:We aimed to examine the distribution of risk alleles in an independent sample and to determine if such genetic components are associated with bone mineral density (BMD) variation in the sample. METHODS:Existing genotype data of 1205 women in the cross-sectional Genomic Wide Scans for Female Osteoporosis Gene Study (GWSFO) were analyzed. Multi-loci genetic risk scores (GRSs) based on 62 BMD-associated single nucleotide polymorphisms (SNPs) were calculated. Regression analysis was employed to assess the association between GRSs and BMD. To examine the effect of SNPs clustered within key pathways associated with the development of osteoporosis, subtype weighted GRS specific to WNT signaling (6 SNPs), RANK-RANKL-OPG (3 SNPs), and mesenchymal stem differentiation (3 SNPs) were generated for analysis. RESULTS:The unweighted GRS ranged from 48 to 80. One third of the women carried 66% risk alleles. After adjusting for age, height, and body weight, each unit increase of weighted GRS was associated with a decrease in BMD of 0.097 at femur (p?<?0.0001) and 0.110 (p?<?0.0001) at lumbar spine. The weighted GRS accounted for only 3.17-4.52% of BMD variance. The WNT signaling pathway GRS (6 SNPs) and the RANK-RANKL-OPG signaling pathway GRS (3 SNPs) both were significantly associated with decreased BMD at femur neck (p?=?0.0004 and p?=?0.0063, respectively) and lumbar spine (p?<?0.0001 and p?=?0.0001, respectively), while the mesenchymal stem cell differentiation pathway (3 SNPs) GRSs were associated only with the lumbar spine BMD (p?=?0.045). CONCLUSIONS:A substantially large percentage of healthy Caucasian women have a high genetic risk of osteoporosis. Weighted GRS was significantly associated with decreased BMD. The contribution of subtype GRS to the BMD variation differs by specific biological pathway and skeletal regions.

Dataset Information

Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women.

Publications

Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women.

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