Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Osteoarthritis Cartilage. Author manuscript; available in PMC Jan 16, 2008.
Published in final edited form as:
Osteoarthritis Cartilage. Aug 2007; 15(8): 972–978.
Published online Apr 6, 2007. doi:  10.1016/j.joca.2007.02.020
PMCID: PMC2204046
NIHMSID: NIHMS29458

Estrogen Receptor alpha genotype is Associated with a Reduced Prevalence of Radiographic Hip Osteoarthritis in elderly Caucasian women

Abstract

PURPOSE

This study evaluated the association between polymorphisms in the ER alpha gene (ESR1) and prevalent and incident radiographic hip OA in a large, well-defined prospective cohort of elderly caucasian women.

METHODS

Prevalent and incident radiographic hip OA (RHOA) was evaluated from all available pelvis x-rays obtained from the Study of Osteoporotic Fractures at baseline and after a mean of 8.3 years. Evaluable DNA samples were available from 4746 of these subjects. RHOA cases were defined by published methods. The ESR1 polymorphisms at intron I (Pvu II for a T/C substitution and Xba I for a A/G substitution) were genotyped in the context of a multiplex PCR amplification followed by allele-specific SNP detection with immobilized oligonucleotide probes in linear arrays. Multiple logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) associated with the T/C and A/G polymorphisms.

RESULTS

RHOA was present in 12.1% of subjects, of whom 325 had JSN score ≥3 and 130 had an osteophyte score ≥2 and JSN score ≥2. There was a significant reduction in the odds of prevalent RHOA for individuals with the C/C compared to T/T genotype at the PvuII site with an Odds Ratio of 0.71 (95% CI: 0.55-0.92) (p=0.01). Adjustments for age, weight, height, hip BMD and estrogen use did not alter the relationship between the C/C genotype and reduced risk of RHOA, with an OR of 0.71 (95% CI: 0.54-0.94) (P=0.01). The risk of incident RHOA was reduced for the Pvu II C/C compared to the T/T genotype (p=0.11). Also, the reduced risk of incident RHOA in C/C subjects varied by estrogen use. There was no association between the Xba I G/G or G/A genotypes and RHOA with OR of 0.82 (95%CI: 0.61-1.10) (p=0.19) compared to women with A/A genotype.

CONCLUSIONS

We conclude that the C/C genotype of the ER alpha Pvu II polymorphism was associated with a modestly reduced risk of prevalent and incident RHOA in elderly caucasian women. Additonal work is required to understand how the intron I ESR1 polymorphism may alter joint degeneration.

Introduction

Osteoarthritis of the hip is a common disease. It increases with age among the elderly population in the United States and accounts for a significant portion of health care burden (1).

Multiple risk factors including age, obesity, tissue injury, and gender, among others, have been well established for hip OA (1). With further investigation, genetics appears to be playing an increasingly larger role in the etiopathogenesis of hip OA (2,3).

Estrogen receptors (ERs) are known to be associated with disease of bone and articular cartilage. The estrogen receptor has two isoforms, alpha and beta. The ER alpha gene (ESR1) is an important mediator of signal transduction, and this protein is expressed in cells of the musculoskeletal system including bone cells and chondrocytes (4). Epidemiology studies have shown that women treated with hormone replacement therapy have a reduced risk of hip OA and hand OA (5-10) but other studies have found short-term of estrogen replacement may increase the risk of hand and hip OA (11-14). The investigators speculated that long term estrogen use was protective of articular cartilage loss or prevented increased bone remodeling around the joint (5-10).

To date, the associations of the ESR1 polymorphisms and knee and hip OA have varied. While some investigators have reported an increased risk of OA of the knee and generalized OA associated with ESR1 polymorphisms (10, 15,16,17), others have not (18,19). The mechanism for this increased risk of OA and the ESR1 polymorphism is not known; however, it could be through its effects of bone or articular cartilage metabolism (18). However, reports of ESR1 polymorphisms and bone metabolism are conflicting with one study reporting increased odds of bone loss and a lower hip bone mineral density over time in individuals with an intronic ESR1 minor allele polymorphism (Pvu II) compared to a control group (20), while another study failed to find an association (21). The purpose of this study was to further evaluate the association between the two widely studied polymorphisms in intron I of the ESR1 (Pvu II and Xba I) with prevalent and incident radiographic hip OA in a large population of elderly Caucasian women from the Study of Osteoporotic Fractures.

Patients and Methods

Study population

All subjects were participants in the Study of Osteoporotic Fractures (SOF), a multi-center cohort study initiated in 1986 to determine risk factors for osteoporotic fractures in elderly women (6, 22). Participants were all age 65 and older at baseline and were recruited from population-based listings at four clinical centers in the United States. Exclusion criteria for the parent study, SOF, included bilateral hip replacement and an inability to walk unassisted; African-American women were excluded because of their low risk of hip fracture. The study was approved by the institutional review board at each of the institutions involved, and all subjects provided written informed consent at enrollment and each clinical examination (22,23).

Buffy coat specimens were collected from a total of 6975 participants at either visit 2 (between 1989-1990) or visit 6 (between 1997-1998), and genotyping was performed in all women who provided adequate consent for genetic studies (Figure 1). Bilateral supine A-P pelvic radiographs were obtained at baseline and at visit 5 (mean of 8.3 years of follow up) (24).

Figure 1Figure 1
Flow sheet of study subjects

The present analysis utilized the visit 5 radiographs to evaluate prevalent RHOA and both the baseline and follow-up radiograph to evaluate incident RHOA.

ER alpha genotyping

The ESR1 polymorphisms were genotyped in the context of a multiplex PCR amplification followed by allele-specific SNP detection with immobilized oligonucleotide probes in linear arrays, as previously described (19, 20). Primers were modified at the 5′ phosphate by conjugation with biotin. Ten to 50 ngs of purified human genomic DNA were amplified in a reaction volume of 50μl with AmpliTaq Gold DNA polymerase using a GeneAmp PCR System 9600 thermal cycler (PE Biosystems, Foster City, CA) with the following cycling profile: an initial hold at 94°C for 7 min, then 33 two-step amplification cycles of 15 sec at 95°C for denaturation and 60 sec at 60°C for annealing /extension, and a final 5-min product extension step at 68°C. Chromogenic detection of allelic variants following stringent hybridization of the biotinylated PCR products to the immobilized sequence-specific probes was performed on a Profiblot II T24 (Tecan, Research Triangle Park, NC). RMS in-house software was used to scan the linear arrays on an Epson Perfection 1670 scanner (Epson, Long Beach, CA) and to assign genotypes. 3,182 samples were genotyped for ER alpha Pvu II twice and 188 for Xba I twice. The agreement between the duplicate genotyping was greater than 95% (23,24).

Radiographic assessments

Prevalent RHOA

Details of radiographic scoring methods for hip OA have been previously described (9,18). Subjects were considered to have prevalent radiographic hip OA at visit 5 (RHOA) if they satisfied at least one of the following three criteria: joint space narrowing (JSN) grade ≥ 3 (range 0-4) which was equivalent to a minimal joint space measurement of 1.5mm or less at either the medial or lateral joint space, a summary grade ≥ 3 (≥3 of 5 individual radiographic features), or both definite (grade ≥ 2) osteophytes (range 0-3) and JSN (range 0-4) in the same hip. For the present study, subjects with a diagnosis of rheumatoid arthritis, Paget’s disease of bone, or bilateral hip replacements were excluded from this analysis (18,24). In this study, 32 subjects had unilateral THRs and for these subjects we used the contralateral hip (non-THR hip) to define RHOA from the visit 5 radiograph (23,24). For each subject, the worst RHOA hip was used in this analysis.

In addition, we further characterized the radiographic phenotype of the RHOA subjects into those with JSN score ≥ 3 (n=325) and those RHOA cases (n=130) that had a femoral osteophyte grade ≥ 2 with JSN ≤ 2 to try to further assess RHOA by phenotype (Figure 1) (23). Reproducibility was good with kappa scores for inter-rater reliability of 0.66 for definite JSN (≥2), 0.71 for definite osteophytes, and 0.65 for summary grades ≥ 2. The intraclass correlation coefficient was 0.85 for the continuous measurement of minimal joint space (6, 23,24).

Incident RHOA

A hip without baseline RHOA was eligible to develop RHOA at the follow-up visit. A hip was defined as having developed RHOA (incident disease) if any of the three findings were present at the 8.3 year follow-up visit in a hip free of all of these findings at baseline, 1) Summary grade >= 2, 2), lateral joint space narrowing grade >=2 or medial joint space narrowing grade >=3 or 3) definite osteophytes >=2 in any location and definite JSN >=2 in any location (26,27).

Covariate assessment

All study participants completed a self-administered questionnaire at the baseline and follow-up visits that included age, Northern European Ancestry, self-reported health status, age at menopause current medication use including current estrogen replacement therapy (ERT), multivitamins, other supplements, and current smoking history. Data presented for study subject characteristics are from visit 5. Height was measured using a wall-mounted Harpenden statiometer (Holtain, Dyfed, U.K.) and weight was measured with a balance beam scale; methods have been previously described (6,26,27). Protocols for bone mineral density measurements of the hip were performed using dual-energy absorptiometry (DXA) (QDR 1000, Hologic, Waltham, MA) and have been previously described as well (9).

Statistical analysis

Differences in subject characteristics and BMD variables between RHOA cases and participants without RHOA were assessed by Students’ t-test for continuous variables and Chi-square tests for dichotomous variables. Hardy-Weinberg equilibrium was assessed in both groups by Chi-square tests, and allele frequencies were calculated using the gene counting method. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for each genotype (for Pvu II TT, TC and CC; for Xba I AA, AG, GG) and the risk of any RHOA, RHOA defined by JSN ≥3 or RHOA defined by femoral osteophytosis of ≥2, and incident RHOA. All analyses for the association of ESR1 Pvu II C/C and C/T and Xba I (G/G and G/A) genotypes and RHOA definitions were performed both with and without adjustments for known and potentially confounding variables including age, height, weight, estrogen use, and femoral neck BMD. Statistical analysis was performed using the statistical software program SAS version 8.2 (SAS Institute, Inc., Cary, NC).

Results

Characteristics of Study Subjects and Genotype Frequencies

Among the 4703 study subjects, 569 satisfied the criteria for RHOA, of which 325 subjects had JSN ≥ grade 3, and 130 had moderate to severe osteophytes (Figure 1). When compared with the 4134 control subjects that did not satisfy the RHOA criteria, the RHOA cases were older, poorer overall health status, and had higher femoral neck BMD (Table 1). All other subject characteristics and BMD variables were not significantly different between the two groups.

Table 1
Subject Characteristics with Radiographic Hip OA and Controls at Visit 5

The frequency of the Pvu II C allele in the cohort was 21.1%, and the frequency of the Xba I G allele in the cohort was 11.8% and both were similar to frequencies observed in similar populations (15,16,17). Genotype frequencies did not deviate from Hardy-Weinberg equilibrium.

Odds Ratios for prevalent RHOA

There was nearly a 30% reduction in the odds of RHOA between the C/C genotype when compared to the T/T genotype at the Pvu II site (p<0.01) (Table 2). Adjustment for age, weight, height, femoral neck BMD, and estrogen use did not alter this association between the C/C genotype and reduced RHOA (p<0.01). A similar reduction was observed with the RHOA phenotype characterized by moderate-to-severe JSN with reduced odds of nearly 35% (p<0.01) for the C/C genotype compared to the T/T, and this remained after adjustment for covariates. There was also a “dose response” with each copy of the C allele and Pvu II, although this association was not significant, No association was observed for the Pvu II genotype and RHOA characterized by moderate to severe osteophytosis.

Table 2
Association between ER alpha (Pvu II ) and RHOA status.

There was an inverse association observed between the Xba I G/G or G/A genotypes and RHOA when compared to the A/A genotype (table 3) although it did not reach statistical significance.

Table 3
Association between ER alpha (Xba I ) and RHOA status.

Incident RHOA

There were 2451 subjects who had no RHOA at the baseline visit and 305 that developed incident RHOA at the follow-up visit. Subjects with the Pvu II C/C genotype had a reduced risk of incident RHOA, of nearly 25% compared to those with the T/T genotype but this difference did not significant (p=0.11). However, subjects with the Pvu II C/C genotype that were on estrogen during the follow-up period (n=452) had over a 30% reduction in risk of incident RHOA compared to subjects with T/T genotype (n=584). (p <0.05) (Table 4). The interaction of prior estrogen use and Pvu II genotype age- adjusted was p=0.73 and for Xba I was p=0.39.

Table 4
Association between ER alpha (Pvu II) and incident RHOA on and off estrogen replacement therapy

Discussion

The present study addressed the association between polymorphisms of ESR1and the risk of RHOA. We found that ESR1 Pvu II SNP (C/C) was associated with reduced prevalence of RHOA and incidence of RHOA by nearly 30%. The reduced odds of prevalent RHOA was most significant in the subgroup of RHOA subjects with moderate to severe joint space narrowing. Since radiographic evidence of joint space narrowing is a surrogate marker for loss of articular cartilage, this polymorphism may protect against cartilage loss. Interestingly, there was no association with the Xba I SNP and RHOA in this population. Lastly, we report that subjects with the Pvu II C/C genotype on estrogen treatment has a modest but significant reduction in the development of incident RHOA compared to subjects without this genotype..

This may be the first study to find a reduced risk of RHOA with the ESR1 Pvu II polymorphism. Ushiyama et al reported an increased risk of generalized OA with the Pvu II and Xba I minor genotypes present with 65 OA patients and 318 controls (16), and Loughlin (19) found no increased risk of idiopathic OA of the hip and knee with the same ESR1 SNPs with 371 OA patients and 369 controls. Bergink et al reported an increased risk of knee OA with Pvu II and Xba I polymorphisms with an odds ratio of 2.2 for homozygotes (Pvu II C/C) and especially for the subgroup of knee OA subjects with osteophytes as the primary radiographic feature (17).

There have been reports that the polymorphisms of the ESR1 are associated with differences in BMD (20,21). Indeed, Bergink et al found a relationship between osteophytes and increased risk of knee OA with ESR1 Pvu II and Xba I polymorphisms (17). They further hypothesized that variations in the ESR1 may be associated with changes in juxtaarticular bone or its response to external forces, rather than articular cartilage and this might lead to more severe OA later in life (17). Interestingly, our group has reported that hip BMD is associated with RHOA in this cohort; however, adjustment for femoral neck BMD did not alter the influence of the Pvu II C/C genotype to reduce the risk of RHOA in our study.

Our observation of a reduced risk of RHOA with ESR1 Pvu II polymorphism was associated with the protection of loss of joint space, a radiographic surrogate for articular cartilage. As this estrogen receptor is found on articular chondrocytes it may be that this polymorphism may be associated with enhanced transcriptional activity or this polymorphism may be in linkage disequilibrium with a functional polymorphism at another location within the ESR1 gene region (9,10). Alternatively, subjects with the C allele of ESR1 may develop more articular cartilage than those without it. However, we did not find a significant difference in articular minimal joint space width, a surrogate measure for the amount of articular cartilage in subjects with the C allele of Pvu II compared to the T/T genotype in our study population.

Since epidemiologic studies report hormone replacement therapy reduce the incidence of hip OA (13), we evaluated if the development of incident RHOA in subjects with the ESR1 Pvu II polymorphism (C/C vs.T/T or C/T) was influenced by ERT. The risk of incident RHOA was reduced about 25% in the subjects with the Pvu II C/C vs. T/T genotype overall, but ERT reduced the risk to greater than 30% in C/C vs. T/T subjects. Other investigators have found that women on ERT with the Pvu II C allele had more protection against fracture risk than the T/T group (28). Also, mesenchymal-stem cell derived osteoblasts (MSCOs) obtained from individuals with the C-allele of ESR1 had a higher basal differentiation capacity of these MSCOs than individuals without the C-allele, however those with the C-allele had higher response to sex steroid treatment. These results could assist in explaining the contradictory effects of ERT on osteoblasts in vitro and in-vivo and also help to explain the different responses to ERT (29)

In addition, Herrington et al found women with the Pvu II polymorphism of ESR1 had a greater increase in high density lipoprotein (HDL) and greater reduction in E-selectin, a soluble adhesion molecule involved in inflammation, on ERT (30,31). These investigators went on to determine whether this intronic SNP had some functional significance and found the C allele produced a favorable and functionally significant binding site for the myb transcription factor. To date there are no data that this genotype is not the functional polymorphism responsible for the observed differential responses. Nonetheless, it could be that this polymorphism is in linkage disequilibrium with another polymorphism that is the functional variant (32). In addition, if OA is a chronic low grade inflammatory disease (33), then the modest reduction in systemic inflammation, e.g, reduced E-selectin levels, in subjects on ERT and with the Pvu II C allele might be the pathway in which these subjects either develop less or have slower RHOA disease progression (30). Additional studies are needed to elucidate these findings.

This study offers several strengths, including its large community-based cohort of elderly Caucasian women and a validated radiographic scoring system that allowed for the construction of phenotype-specific definitions to fully characterize the extent of RHOA. However, there are also several potential limitations. Our radiographic definitions of RHOA may not be comparable to other grading schemes. Also, despite the large number of subjects with DNA and a hip radiograph available for scoring OA, we only had 569 subjects with RHOA and the numbers of participants were smaller when we subdivided by either genotype, individual radiographic features or disease progression. However, with our study sample size we had over 90% power confirm or refute our stated hypothesis for prevalent disease and greater than 80% for incident disease. This study population was limited to Caucasian women aged 65 years and older and we only evaluated one anatomic site for OA. Our findings may not be generalized to other populations or to other anatomic sites for OA such as the knee and the hand. Also, population stratification is an often cited limitation of candidate gene studies because population stratification can contribute to false positive associations and an inability to reproduce findings(34). Women in the present study were recruited from several clinical centers in the U.S. and any resultant population stratification could have in principle produced false-positive results. However, adjusting for study center and northern European ancestry had no effect on our findings.

In summary, we found that the Pvu II C/C genotype of the ESR1 was associated with a modestly reduced risk of prevalent and incident RHOA. Our findings differ from those reported for this polymorphism in knee OA and generalized OA in other populations. Additional work is now required to determine why this polymorphism prevents radiographic hip OA development.

Acknowledgments

This work was supported by grants from the NIH 1R01AG05407, 1R01AR40431, the Doris Duke Clinical Research Fellowship (CRF) Program for Medical Students #20000684, the Rosalind Russell Arthritis Research Foundation, and funding from Roche Molecular Systems

Footnotes

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