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Single nucleotide polymorphisms of estrogen receptors are risk factors for the progression of adolescent idiopathic scoliosis: a systematic review and meta-analyses

Journal of Orthopaedic Surgery and Research volume 19, Article number: 605 (2024) Cite this article

Abstract

Background

There have been some studies on the occurrence of ESR1 and 2 polymorphisms and AIS, but some data extraction is wrong, and there are no studies on the progress of AIS.

Methods

Computer searches were conducted on PubMed, EMBASE, ScienceDirect and Scopus from the establishment of the database to April 2024. Cross-sectional and case-control studies on estrogen receptor ESR1, two single nucleotide polymorphisms, and the occurrence and development of AIS were collected, and statistical analysis was performed using the Revman 5.3 software.

Results

In the comparison of the association between single nucleotide polymorphisms of estrogen receptors ESR1 and 2 and the occurrence and development of AIS, eight studies were included, including 2706 cases and 1736 controls.The results showed that the AA genotype [OR = 0.50,95%Cl(0.34,0.72),P = 0.0003] at the XbaI locus of ESR1,CC genotype [OR = 1.67,95%Cl(1.16,2.42), P = 0.006], C allele [OR = 1.28,95%Cl(1.03,1.59),P = 0.03], and T allele [OR = 0.78,95%] Cl(0.63,0.97),P = 0.03] at the PvuII locus of ESR1 and TT genotype [OR = 0.50,95%Cl(0.26,0.93),P = 0.03] at the AlwNI locus of ESR2 showed statistically significant differences between the progressive and stable AIS patients.

Conclusion

Single nucleotide polymorphisms of ESR1 and ESR2 were not related to the occurrence of AIS; however, some of them were related to the progression of AIS.

Background

Adolescent idiopathic scoliosis (AIS) is a common problem that primarily affects young people aged 10 years to the end of their growth period, accounting for 84–89% of all types of scoliosis [1]. Progressive scoliosis and treatable scoliosis are more common in girls than in boys, and studies have shown that [2] this disease has strong genetic factors, with most researchers tending to believe that multiple factors are involved in the occurrence of AIS. Although extensive research has been conducted since 1986, the etiology of scoliosis remains unclear.

The severity of scoliosis in adolescents is often determined by the Cobb angle. When the upper and lower limits of the patient’s deformity angle (Cobb angle) and the curvature of the spine on the coronal plane are greater than 10° [3], AIS is diagnosed and classified as mild to moderate to severe on the basis of the Cobb angle [4]. Studies have indicated that adolescents with Cobb angles ≤ 20° are between 10% and 20% more likely to experience progression, whereas in adolescents with scoliosis curvature greater than 20° and immature bone status, the likelihood of progression may be 70% or greater, indicating that AIS patients are more prone to progression with a larger Cobb angle [5]. The treatment guidelines of the Scoliosis Research Society (SRS) have explicitly identified the Cobb angle as the primary outcome for evaluating treatment efficacy [6]. Therefore, this study used the Cobb angle as an indicator to evaluate the progress of AIS.

It is widely recognized that there is a relationship between AIS and estrogen levels in humans. Therefore, we incorporated estrogen into our study to determine its association with AIS. Given the limited and inconsistent research on the effect of estrogen on AIS [7, 8], both high and low estrogen levels appear to promote the occurrence and development of AIS to some extent. This result may be related to its interaction with receptors during signal transduction. Therefore, further research and analysis should be conducted on the effects of estrogen receptors (ESRs) on the development of AIS. ESRs can be divided into two main types, ESR1 and ESR2, and their gene polymorphisms, ranging from single nucleotide polymorphisms to methylations [9, 10], have been extensively studied in recent years [11]. Single nucleotide polymorphisms (SNPs) in ESR1 are concentrated mainly at the XbaI (A/G rs9340799) and PvuII (C/T rs2234693) loci, whereas ESR2 studies have focused mainly on exon AlwNI (C/T rs1256120). Existing studies [11,12,13,14,15] are based mainly on analyses of the relationships between the SNPs of these three loci and the incidence rate of AIS, and most of the results of meta-analyses are not significantly different. However, in the research process, the data from Kotwicki [12] in the meta-analysis of ESR2 were incorrectly recorded in the CC and TT groups, making the only published meta-analysis of the association between ESR2 single nucleotide polymorphisms and AIS lose its reference value.

At present, there is almost no published research on the relationships between these three loci and the progression of AIS. This study focused on the relationship between nucleotide polymorphisms of these three loci and AIS progression and explored whether the different genotypes of these three loci affect the progression of the Cobb angle in patients with AIS. Simultaneously, the relationships between these three loci and the incidence of AIS will be further investigated, ESR2 data with errors and omissions will be corrected, and a meta-analysis will be performed again.

Methods

This study was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16]. This study is registered with PROSPERO (ID: CRD42024538151).

Search strategy

PubMed (no language or time limit, and the time period is until April 2024); EMBASE (no language or time limit, and the time period is until April 2024);ScienceDirect (no language or time limit, and the time period is until May 2024);Scopus (no language or time limit, and the time period is until May 2024).

Study selection

The authors independently shifted the search results. Differences in the selection process were resolved through discussions until a consensus was reached. First-level filtering involves evaluating all the available information returned by an electronic search (i.e., summaries, titles, and keywords). Level 2 screening includes evaluating the full-text reports of studies deemed likely to qualify after Level 1 screening or studies for which there is insufficient information available to determine eligibility (e.g., no abstract).

Studies that met the following criteria were included in the evaluation:

The selected literature is a retrospective study on estrogen, estrogen receptor number and structural changes and the incidence and progression of AIS in adolescents with scoliosis. The study subjects were mainly patients with AIS, were aged less than 20 years, and were mainly female. There was no publication time limit.

Studies that met the following criteria were excluded:

Study design: other observational study designs, clinical trials, or reviews.

The study content was not associated with AIS or was associated with AIS but did not provide specific data

There were no further eligibility restrictions on population characteristics, study design details, phenotypic diagnostic procedures, molecular methods of genotyping, language, or publication date.

However, the summary of the meeting was excluded (see Fig. 1).

Fig. 1
figure 1

Flow diagram of the study identification and selection process

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Methodological quality assessment

Two authors conducted the literature review. As all the studies included in this review were cross-sectional, the AHRQ cross-sectional study evaluation criteria were adopted. The United States Agency for Healthcare Research and Quality (AHRQ) recommends quality evaluation criteria for observational and cross-sectional studies. The standard consists of 11 items with “yes,” “no” and “unclear” answers [17]. The quality analysis evaluation table can be found in Table 1.

Data extraction

The following information was extracted from the included studies:

  1. 1)

    Author;

  2. 2)

    Year of publication;

  3. 3)

    Subject characteristics (such as the number of cases and controls, age, sex, and ethnic composition).

  4. 4)

    Genotyping methods, including blind status and quality assurance or control procedures;

  5. 5)

    Cobb angle number and corresponding progress information.

  6. 6)

    Allele/genotype frequency. The authors extracted the data independently, and differences were resolved through discussion and consensus.

Statistical analysis

Relevant data were extracted from the abovementioned literature, met the requirements, and input into Review Manager 5.3 (RevMan, The Cochrane Collaboration, Oxford, UK). Quantitative data were selected as continuous variables for analysis. Qualitative data were analyzed via binary categorical variables. According to the principle of the heterogeneity test, if the calculation results showed that the heterogeneity of each study was small, the fixed-effects model was used for analysis; if the heterogeneity was large, the random-effects model was used for analysis [17, 18]. The corresponding analysis model was selected according to the specific I2 values of various data and their corresponding values.

Since most of the studies included in the meta-analysis were retrospective etiological studies, we selected the odds ratio (OR, also known as the odds ratio) as the test statistic for binary classification variables and calculated a 95% confidence interval. For continuous variables, either the mean difference (MD) or standardized mean difference (SMD) was used as the effect size, and 95% confidence intervals were calculated. A sensitivity analysis was performed by comparing the calculated results of the two different effect models. The risk bias of the included studies was assessed via the bias risk assessment map of Reviw Manager software. The combined statistics were considered to be statistically significant at P < 0.05.

Results

Study inclusion and characteristics

Through searches according to the above requirements, 585 studies were preliminarily retrieved. After two researchers carefully read the title and abstract of the literature, a total of 548 cross-sectional studies with irrelevant content were excluded. 37 articles on estrogen receptors and AIS. After further screening 37 studies to exclude reviews, duplicate studies and meta-analyses, as well as some studies unsuitable for meta-analysis due to insufficient data, 8 studies were ultimately included in the meta-analysis to study the effects of ESR1 and 2 site-specific single nucleotide polymorphisms on the occurrence and development of AIS. Among the eight papers, three studied only both sites of ESR1, the other two studied XbaI or PvuII in ESR1, and the other two studied only the middle sites of ESR2. One paper studied the influence of all key single nucleotide polymorphisms in ESR1 and ESR2 on AIS. Detailed information can be found in the following table.

Table 1 Quality analysis of the included literature
Full size table

General characteristics of the studies

Details can be found in Table 2 at the end of this article.

Table 2 Features and relevant information of the included literature-ESR
Full size table

ESR1

Meta-analysis of various genotypes and alleles of XbaI and PvuII yielded the following results:

Details can be found in Table 3 at the end of this article.

As shown in Table 3, after summarizing and analyzing the distribution of each genotype and corresponding alleles at the XbaI and PvuII loci of ESR1 in the case and control groups, the result was P > 0.05, indicating that the XbalI and PvuII mutations of ESR1 were not associated with AIS susceptibility. This result is consistent with the results of several related studies in recent years [25].

The influence of the Xbal and PvuII sites on AIS progression was further analyzed. Owing to the different representations of the corresponding progression in different institutes, they were classified into two categories for the convenience of the study: the groups with Cobb angle progression > 5°, initial Cobb angle ≥ 40° in the case group, and monthly progression greater than 1° were uniformly classified into the progression group. The groups whose Cobb angle progress was less than or equal to 5°, whose initial Cobb angle in the case group was less than 40°, and whose Cobb angle progress was less than or equal to 1° per month or no progress were all regarded as the stable group.

As seen from the results of the progression association in Table 3, there was still no statistical correlation between each genotype or allele of XbaI and progression (P > 0.05). However, for PvuII, there were significant differences between the CC genotype, C and T alleles, AIS progression, and stable groups (P < 0.05). It has been suggested that there is a correlation between the CC genotype and the C and T alleles and the progression of AIS in PvuII of ESR1. The progression of the Cobb angle in AIS patients with the CC genotype at PvuII may be larger and faster, and the C allele at this locus promotes Cobb angle progression in AIS patients. The T allele is a protective gene for Cobb angle progression. Figures 2 and 3, and 4 show detailed forest comparison maps for the corresponding groups.

Fig. 2
figure 2

CC genotype of PvuII

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Fig. 3
figure 3

C allele gene at PvuII

Full size image
Fig. 4
figure 4

T allele gene at PvuII

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Table 3 The relationship between SNPS of ESR1 and the occurrence and development of AIS
Full size table

According to some studies [26], XbaI is often used to evaluate the AIS progress of Asian population, so the following results were obtained through the meta-analysis of the two studies of Wu and Inoue, in particular.

As shown in Table 3, in studies in the Asian population, the AA genotype at the XbaI locus of ESR1 was significantly different between the AIS progression group and the AIS stable group (P = 0.0003 < 0.05), whereas the other genotypes were not significantly different. These results indicate that Asian patients with AA genotype at XbaI are less likely to progress.

Figure 5 show detailed forest comparison maps for the corresponding groups.

Fig. 5
figure 5

AA genotype of Xba1

Full size image

ESR2

The following results were obtained from the analysis of the AlwNI-related genes of ESR2:

Details can be found in Table 4 at the end of this article.

As shown in Table 4, there was no significant difference in the distribution of the AlwNI genotypes and alleles between the AIS and control groups (P > 0.05). Therefore, the single nucleotide polymorphism of AlwNI does not correlate with the occurrence of AIS.

To exclude the influence of men, the following table results were reanalyzed to exclude men in particular, and it can be seen that there is still no association, but the effect seems to be greater in women.

According to the relationship with progression shown in Table 4, there was no statistical correlation between the CT and CC genotypes and the C and T alleles and progression in AlwNI (P > 0.05). However, a significant difference was observed between the CC genotype and AIS progression in the stable group (P < 0.05). A correlation was observed between the TT genotype and AIS progression in the AlwNI of ESR2, indicating that patients with the TT genotype were less likely to experience AIS progression. Figure 6 shows a detailed forest comparison map of the corresponding groups.

Fig. 6
figure 6

TT genotype of AlwNI

Full size image
Table 4 Results of meta-analysis of AlwNI of ESR2 by genotype and allele ratio in AIS group and control group
Full size table

Discussion

Previous studies [7, 8] have shown that the influence of estrogen on AIS is often inconsistent, and both high and low estrogen levels seem to promote the occurrence and development of AIS to some extent, which may be related to its interaction with receptors in the process of signal transduction. Therefore, the next step is to conduct further research and analysis on the influence of estrogen receptors on the development of AIS. Previous studies [13, 14, 27,28,29,30,31,32] have confirmed that the distribution of estrogen receptors affects the occurrence and progression of AIS at the experimental level. Estrogen receptor gene polymorphisms also regulate the expression of estrogen receptors in real time; thus, recent studies [15] have focused mainly on nucleotide polymorphisms of estrogen receptor genes. In 2002, Inoue analyzed the distribution of Xbal and PvuII genotypes in AIS patients and proposed the influence of polymorphisms of two gene loci on the onset and progression of AIS. Subsequently, Wu, Tang, and Takahashi conducted repeated tests on the corresponding sites of ESR1, among which only Wu’s study results were verified for Inoue’s study, and the other groups showed no significant difference between the two. At present, only three studies have investigated ESR2, with the exception of the first experiment by Zhang, which suggested that the difference was statistically significant; the other two studies have not been confirmed. Part of the reason may be that there are certain false positives in the first of the two articles; for example, Takahashi’s article mentioned that the data collected by Inoue did not meet the HWE standard. In addition, owing to the problem of data registration errors in Zhao’s previous study, the results obtained in this study are the first in major journals to conduct an accurate meta-analysis of rs1256120 of ESR2, which has high reference value. In recent years, many studies [11, 15] have been conducted on SNPs polymorphisms at the corresponding loci of ESR1 and ESR2, and a meta-analysis has been conducted on the correlation between the loci involved in this study and the incidence of AIS; however, few studies have analyzed the progression of AIS at the corresponding loci. In this study, we conducted the first ESR meta-analysis of AIS progression with Cobb angle as the investigation object.

According to Wang’s study [26], in clinical practice, susceptibility sites, including rs9340799 in ESR1 and rs1256120 in ESR2, can predict the progression of AIS. However, researchers have not reached a consensus on these loci as modifiers of curve progression, and the correlation between ESR1 and ESR2 and AIS progression is only a summary analysis of previous studies without meta-analysis results as evidence. In this study, the ability of XbaI to predict AIS progression in Asian populations was demonstrated. However, whether the phenomenon that has not been repeated in other populations is due to human causes still needs to be supported by more Asian population research data.On the other hand, this has led to a discussion about whether racial differences affect the progression and correlated outcomes of ESRs and AIS. The answer is yes. Some studies [23, 33, 34] on European populations have shown that XbaI has no effect on the progression and occurrence of AIS, while some studies based on European populations have also confirmed the correlation between XbaI and AIS progression. The reason is not only that the genetic distribution of ESR gene itself [34] is different in different populations, but also that living environment, work and rest habits and other external factors [35, 36] have an impact on gene expression.

This study further verified the role of rs9340799 in ESR1 and rs1256120 in ESR2 in predicting AIS progression through meta-analysis, providing more theoretical support, and the potential of ESR1 PvuII (C/T rs2234693) in predicting AIS progression was also determined, which could improve the accuracy of predicting AIS progression together with other SNP loci in the future. As estrogen receptor modulators such as raloxifene have been widely used to control AIS progression, the estrogen receptor genotypes of adolescent patients can also be used to evaluate the prognosis of patients receiving raloxifene drugs, facilitating the selection of appropriate drugs for individual treatment. For patients with risk genotypes, AIS may progress at a faster rate. Timely genetic diagnosis after diagnosis can enable timely intervention at an early stage to prevent the progression of AIS in a more targeted manner.

This study combined the significance of the Cobb angle in the progression of AIS and concluded that there is a correlation between mutations related to the PvuII site in the ESR1 and ESR2 AlwNI upper sites and AIS progression. However, considering that the induction method for AIS progression in this study was relatively general, the Cobb angle in different patients may have affected the future progression rate of this patient to some extent. For example, patients with larger Cobb angles may have relatively slow or fast disease progression rates. This may have led to errors in the experimental results, resulting in false positive results. Further rigorous research should be conducted to confirm whether a correlation exists between the two variables.

Conclusion

In this study, we confirmed the association of ESR1 XbaI with AIS progression in the Asian population through meta-analysis, and the association of PvuII and ESR2 AlwNI with AIS progression. Such findings are conducive to the construction of future research models for predicting AIS progression, and can better prevent the progression of AIS patients.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AIS:

Adolescent idiopathic scoliosis

ESR:

Estrogen receptor

SRS:

Scoliosis Research Society

SNPs:

Single nucleotide polymorphisms

AHRQ:

The United States Agency for Healthcare Research and Quality

OR:

Odds ratio

MD:

Mean difference

SMD:

Standardized mean difference

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Acknowledgements

In the writing of this paper, we received careful guidance from Professor Xu Yi, who patiently provided us with guidance and opinions from the beginning of setting the direction and during the process of researching and preparing materials. Here, we express our sincere gratitude and heartfelt wishes to Professor Xu. School-level Project of Innovation and Entrepreneurship Training Program for College Students of Sun Yat-sen University in 2024 (No.20242105); Project of the National Natural Science Foundation of China, Study on the mechanism of disease progressionand biomechanical Intervention of the three elements of “spinal -Lower limb -brain network"based onMathematical modeling for Idiopathic scoliosis (Project approval number:82172548).

Funding

School-level Project of Innovation and Entrepreneurship Training Program for College Students of Sun Yat-sen University in 2024 (No.20242105); Project of the National Natural Science Foundation of China, Study on the mechanism of disease progressionand biomechanical Intervention of the three elements of “spinal -Lower limb -brain network” based on Mathematical modeling for Idiopathic scoliosis (Project approval number:82172548).

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  1. Xuan Li

    Present address: The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628, Zhenyuan Road, Xinhu Street, Guangming District, Shenzhen City, Guangdong Province, China

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  1. The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628, Zhenyuan Road, Xinhu Street, Guangming District, Shenzhen City, Guangdong Province, China

    Jingyi Rao, Shuping Qian & Yi Xu

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Rao and Qian are responsible for researching, screening materials, and writing papers, Xu is responsible for determining research directions and providing support when it is necessary, and Li is responsible for reviewing.

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Correspondence to Yi Xu.

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Rao, J., Qian, S., Li, X. et al. Single nucleotide polymorphisms of estrogen receptors are risk factors for the progression of adolescent idiopathic scoliosis: a systematic review and meta-analyses. J Orthop Surg Res 19, 605 (2024). https://doi.org/10.1186/s13018-024-05102-2

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Keywords

Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X