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Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians.

Velasco J, Hernández JL, Pérez-Castrillón JL, Zarrabeitia MT, Alonso MA, González-Macías J, Riancho JA - BMC Med. Genet. (2010)

Bottom Line: In the sex-stratified analysis, the association was significant in females, but not in males.No genotype-related differences in gene expression were found in 42 femoral bone samples.However, there are marked differences in allele frequencies between Asian and Caucasian populations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, Hospital U,M, Valdecilla, University of Cantabria, RETICEF, Santander, Spain.

ABSTRACT

Background: Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (ESR1) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians.

Methods: We analyzed those two SNPs and another neighbour SNP located on the exon 4 of ESR1 in 787 patients with hip fractures and 953 controls from Spain.

Results: The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples.

Conclusions: This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of ESR1 and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.

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Related in: MedlinePlus

ESR1 haplotypes and hip fractures. Diagram showing the association of 2-SNP (rs3020314 and rs1884051) and 3-SNP (rs1801132, rs3020314 and rs1884051) haplotypes with hip fractures in the whole group of men and women combined and in the female group. The numbers represent the p-values of the omnibus χ2 test including all haplotypes and the result for the individual haplotype showing the most significant association. The upper part of the figure shows the between-locus linkage disequilibrium (D').
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Figure 1: ESR1 haplotypes and hip fractures. Diagram showing the association of 2-SNP (rs3020314 and rs1884051) and 3-SNP (rs1801132, rs3020314 and rs1884051) haplotypes with hip fractures in the whole group of men and women combined and in the female group. The numbers represent the p-values of the omnibus χ2 test including all haplotypes and the result for the individual haplotype showing the most significant association. The upper part of the figure shows the between-locus linkage disequilibrium (D').

Mentions: The mean age of patients was 83 ± 8 yr; age of controls was 74 ± 9 yr. Patients with fractures had more frequent comorbid diseases (table 1). The allelic frequencies are shown in table 2. They were similar to those reported in the Caucasian Hapmap database, but rather different from the frequencies in Asian populations. There was no evidence for departure from the Hardy-Weinberg equilibrium. The three SNPs studied were in linkage disequilibrium, with D' values between 0.79 and 0.94, and r2 values between 0.44 and 0.76 (figure 1). Loci rs3020314 and rs1884051 were considered as a haplotypic block according to the 4-gamet rule.


Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians.

Velasco J, Hernández JL, Pérez-Castrillón JL, Zarrabeitia MT, Alonso MA, González-Macías J, Riancho JA - BMC Med. Genet. (2010)

ESR1 haplotypes and hip fractures. Diagram showing the association of 2-SNP (rs3020314 and rs1884051) and 3-SNP (rs1801132, rs3020314 and rs1884051) haplotypes with hip fractures in the whole group of men and women combined and in the female group. The numbers represent the p-values of the omnibus χ2 test including all haplotypes and the result for the individual haplotype showing the most significant association. The upper part of the figure shows the between-locus linkage disequilibrium (D').
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837017&req=5

Figure 1: ESR1 haplotypes and hip fractures. Diagram showing the association of 2-SNP (rs3020314 and rs1884051) and 3-SNP (rs1801132, rs3020314 and rs1884051) haplotypes with hip fractures in the whole group of men and women combined and in the female group. The numbers represent the p-values of the omnibus χ2 test including all haplotypes and the result for the individual haplotype showing the most significant association. The upper part of the figure shows the between-locus linkage disequilibrium (D').
Mentions: The mean age of patients was 83 ± 8 yr; age of controls was 74 ± 9 yr. Patients with fractures had more frequent comorbid diseases (table 1). The allelic frequencies are shown in table 2. They were similar to those reported in the Caucasian Hapmap database, but rather different from the frequencies in Asian populations. There was no evidence for departure from the Hardy-Weinberg equilibrium. The three SNPs studied were in linkage disequilibrium, with D' values between 0.79 and 0.94, and r2 values between 0.44 and 0.76 (figure 1). Loci rs3020314 and rs1884051 were considered as a haplotypic block according to the 4-gamet rule.

Bottom Line: In the sex-stratified analysis, the association was significant in females, but not in males.No genotype-related differences in gene expression were found in 42 femoral bone samples.However, there are marked differences in allele frequencies between Asian and Caucasian populations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, Hospital U,M, Valdecilla, University of Cantabria, RETICEF, Santander, Spain.

ABSTRACT

Background: Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (ESR1) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians.

Methods: We analyzed those two SNPs and another neighbour SNP located on the exon 4 of ESR1 in 787 patients with hip fractures and 953 controls from Spain.

Results: The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples.

Conclusions: This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of ESR1 and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.

Show MeSH
Related in: MedlinePlus