|Year : 2022 | Volume
| Issue : 3 | Page : 318-324
Polymorphisms in paired box 1 gene were associated with susceptibility of adolescent idiopathic scoliosis: A case–control study
Antônio Eulálio Pedrosa1, Gustavo Borges Laurindo de Azevedo1, Jessica Vilarinho Cardoso2, João Antonio Matheus Guimarães3, Helton Luiz Aparecido Defino4, Jamila Alessandra Perini5
1 Spine Surgery Center, National Institute of Traumatology and Orthopaedics (INTO), Rio de Janeiro, RJ; Departments of Orthopaedic and Anesthesiology, Ribeirão Preto Medical School, University of São Paulo, de São Paulo-Brazil, Brazil
2 Research Laboratory of Pharmaceutical Sciences (LAPESF), State University of Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
3 Research Division of National Institute of Traumatology and Orthopaedics (INTO), Rio de Janeiro, RJ, Brazil
4 Departments of Orthopaedic and Anesthesiology, Ribeirão Preto Medical School, University of São Paulo, de São Paulo-Brazil, Brazil
5 Research Laboratory of Pharmaceutical Sciences (LAPESF), State University of Rio de Janeiro (UERJ); Research Division of National Institute of Traumatology and Orthopaedics (INTO), Rio de Janeiro, RJ, Brazil
|Date of Submission||14-Apr-2022|
|Date of Acceptance||09-May-2022|
|Date of Web Publication||14-Sep-2022|
Jamila Alessandra Perini
Pharmaceutical Sciences Research Laboratory (LAPESF), State University of Rio de Janeiro (UERJ) (https://lapesfuezo.wixsite.com/website), Av. Manuel Caldeira de Alvarenga, 1.203. Zip-code: 23070-200, Rio de Janeiro
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Association of genetic polymorphisms in paired box 1 (PAX-1) gene can influence the development of adolescent idiopathic scoliosis (AIS). PAX-1 is mainly expressed in the region of the vertebral bodies and intervertebral discs, being important for the proper formation of spinal structures.
Objectives: The objective of this study was to evaluate the association of polymorphisms in PAX-1 gene with the susceptibility of AIS.
Settings and Design: This was an analytical observational case–control study.
Materials and Methods: Samples of 59 AIS indicated for surgical treatment, and 119 controls, without spinal disease were genotyped for PAX-1 rs6137473 and rs169311 polymorphisms.
Statistical Analysis: The association of the polymorphisms with AIS was evaluated by a multivariable logistic regression model, using odds ratios (OR) and 95% confidence intervals (CI).
Results: According to Lenke's classification, 89.8% had Type I and 10.2% II curves. The mean value of the Cobb angle of the proximal thoracic curve was 30.8°, 58.7° thoracic, and 30.4° for the lumbar and on the bending films 14.6°, 40.7°, and 11°, respectively. Among the AIS group, there was a predominance of females (8.8:1). The PAX-1 rs169311 and rs6137473 polymorphisms were positively associated with developing the AIS (OR = 1.98; 95% CI = 1.2–3.3 and OR = 3.16; 95% CI = 1.4–7.3, respectively). The rs6137473 polymorphism was associated with the lumbar modifier B and C compared to A (OR = 2.52; 95% CI = 1.1–5.8).
Conclusions: PAX-1 polymorphisms were associated with an increased risk of developing the AIS and with curve severity and can be used as a biomarker to map the risk of developing surgical-grade AIS, guiding the treatment of patients.
Keywords: Adolescent idiopathic scoliosis, genetic polymorphisms, Lenke's classification, paired box 1
|How to cite this article:|
Pedrosa AE, Azevedo GB, Cardoso JV, Guimarães JA, Defino HL, Perini JA. Polymorphisms in paired box 1 gene were associated with susceptibility of adolescent idiopathic scoliosis: A case–control study. J Craniovert Jun Spine 2022;13:318-24
|How to cite this URL:|
Pedrosa AE, Azevedo GB, Cardoso JV, Guimarães JA, Defino HL, Perini JA. Polymorphisms in paired box 1 gene were associated with susceptibility of adolescent idiopathic scoliosis: A case–control study. J Craniovert Jun Spine [serial online] 2022 [cited 2023 Mar 23];13:318-24. Available from: https://www.jcvjs.com/text.asp?2022/13/3/318/355988
| Introduction|| |
The curve progression in adolescent idiopathic scoliosis (AIS) depends on several factors such as skeletal age, sex, magnitude, and type of curves.,,, Only 0.1% of patients have surgical treatment indication (Cobb angle >40°), and according to Lenke's classification, Types I and II are the most common phenotypes.,
Although the etiology of AIS is still unknown, there are some theories that try to explain the onset of the disease, such as metabolic errors, nervous system dysfunction, biomechanical, bone growth, and genetic alterations. Several candidate genes, associated with the AIS development, participate in the formation of the intervertebral disc, among them paired box 1 (PAX-1) stands out,,,, due to its predominant expression in the region of the vertebral bodies and intervertebral discs, being crucial for the proper formation of spinal structures.,
The PAX-1 gene is a transcription factor, characterized by the presence of a conserved DNA-binding domain, located on chromosome 20p11. Considering the single-nucleotide polymorphisms (SNPs) described in the PAX-1 gene, which have already been associated with the AIS development, the rs6137473 A>G and the rs169311 C>A SNPs stand out, mainly because of their ability to affect the PAX-1 expression and because of the availability of previous studies describing this association.,,, The aim of this study was to describe the clinical data of Lenke I and II AIS patients and to evaluate the association of PAX-1 rs6137473 and rs169311 SNPs with the development and severity of the disease.
| Materials and Methods|| |
An analytical observational case–control study was carried out in a sample of patients diagnosed with AIS, treated by the Spine Surgery Service of a public orthopedic referral hospital in Brazil, in the period from July 2018 to January 2019. The study was conducted in accordance with the Helsinki Declaration and with the ethical standards.
All included patients (N = 59) were over 10 years old and were clinically diagnosed with AIS, classified as Lenke type I and II, with Cobb angle >40° and coronal decompensation, with the intention of homogenizing the scoliosis phenotype, since both forms have a lumbar curve flexible. Patients with incomplete radiographic data, absence of biological material for genetic analysis, or those with any underlying disease that could justify nonidiopathic scoliosis, such as neurological disorders, neuromuscular disorders, and syndromic diseases, were excluded. In the control group (N = 119), healthy volunteers recruited at INTO's blood bank without spinal disease were included.
Panoramic radiographs of the spine in AP, lateral, and supine bending tests [Figure 1] were taken to define the Cobb angle and to identify the patients classified as Lenke 1 and 2, the lumbar modifiers (A, B, and C), and the sagittal modifiers, according to the thoracic kyphosis angle measured from T5–T12 (being hyper for kyphosis >40°; hypo, <10°; and normal, when kyphosis is between 11° at 40°)., The evaluation of radiographs was performed using the Surgimap Spine software (Nemaris Inc., New York, USA), version 184.108.40.206.
|Figure 1: Spine radiographs of scoliosis patients. (a-d) Cobb angle measurements. (a) Posteroanterior radiograph with proximal thoracic (white lines), main thoracic (red lines), and thoracolumbar curves (yellow lines) measured. (b) Left-side bending radiograph showing proximal thoracic (white lines) and thoracolumbar flexibility (black lines). (c) Right-side bending radiograph showing main thoracic curve flexibility. (d) Lateral spine radiograph showing thoracic kyphosis measured from T5 to T12|
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Genomic DNA was extracted from an oral mucosal sample using the Invisorb® Spin DNA Extraction Kit (Qiagen, Hilden, Germany), according to the procedures recommended by the manufacturer. Analysis of the rs6137473 and rs169311 SNPs of the PAX-1 gene was performed by the real-time polymerase chain reaction (PCR) technique using the QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA USA). PCR amplification was performed in 8-μL reactions with ~30 ng of template DNA, ×1 TaqMan Universal Master Mix (Applied Biosystems, Foster City, CA, USA), ×1 each primer and probe assay. Thermal cycling was initiated with a first denaturation step of 10 min at 95°C, followed by 40 cycles of denaturation at 92°C for 15 s and annealing at 60°C for 1 min. To assure genotyping quality, in each reaction, two standardized negative and positive controls of each polymorphism genotype were used, as previously described.
A descriptive analysis about demographic and clinical data of population studied was performed, using relative frequencies for each categorical variable. Continuous variables were presented as mean ± standard deviation and differences between means were evaluated using Student's t-test. Categorical data were expressed as percentages and evaluated by Person's Chi-square test (x2) or Fisher's exact test, when necessary.
The allelic and genotypic frequency of the studied polymorphisms was determined by direct gene counting and the Hardy–Weinberg equilibrium (HWE) was calculated by the Chi-square test for goodness-of-fit. To assess the association of polymorphisms with the development and severity of AIS, the odds ratios with their respective 95% confidence intervals were estimated and P < 0.05 was considered statistically significant. A binary logistic regression model was performed to control for possible confounding factors, considering the biological and statistical significance of the univariate analysis of each sociodemographic and clinical variable. A value of P ≤ 0.25 was considered the input significance level and P ≤ 0.05 as the output significance for the final regression model. The Statistical Package for Social Sciences program (SPSS Inc., Chicago, IL, USA, version 20.0) was used for all statistical analyses.
| Results|| |
Radiographic data of adolescent idiopathic scoliosis
Of the 59 patients, 89.8% (N = 53) were classified as Lenke type I and 10.2% (N = 6) as Lenke II. Lumbar modifier A was observed in 67.8% (N = 40) of patients, followed by modifiers B (N = 16, 27.1%) and C (n = 3 or 5.1%). There was a predominance of the normal type (74.6%, N = 44), 23.7% hyperkyphotic (N = 14), and 1.7% hypokyphotic (N = 1) for the sagittal modifier. Considering the lumbar and sagittal modifier, the most frequent form of AIS was the normal Lenke IA (N = 25, 42.4%), followed by normal Lenke IB (N = 13, 22.0%) and hyperkyphotic Lenke IA (N = 8, 13.6%). Only one patient (1.7%) had a hypokyphotic Lenke IA and another one had a hyperkyphotic Lenke IC (1.7%). Three patients (5.1%) were classified as Lenke IB hyperkyphotic and another two (3.4%) as IC normal. Of the Lenke II, four patients (6.8%) were classified as A (normal) and two (3.4%) as A hyperkyphotic [Figure 2]. The Cobb angles of proximal thoracic, main thoracic, thoracolumbar/lumbar of the 59 AIS patients are shown in [Table 1].
|Figure 2: Adolescent idiopathic scoliosis patients (n = 59) distribution categorized by Lenke's classification system. A, B, and C are the lumbar spine modifier. Type Lenke I main thoracic and Lenke II double thoracic curves|
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|Table 1: Curve angle information (proximal thoracic, main thoracic, thoracolumbar/lumbar) of adolescent idiopathic scoliosis patients|
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Case–control study and polymorphisms association
Approximately 89.8% (N = 53) of AIS cases were female (8.8:1), with a mean age of 22.8 ± 5.7 years at recruitment, 42.4% (N = 25) aged 20 years old or less, and 79.7% (N = 47) with low weight or normal BMI (21.5 ± 5.2 Kg/m2). The control group (N = 119) consisted of 108 women (90.8%), with a mean age of 28.6 ± 6.6 years and a mean BMI of 25.7 ± 4.4 Kg/m2. All variables with P ≤ 0.25 were inserted in the logistic regression model to identify possible confounding factors involved with the association between SNPs and AIS. After multivariate analysis, the variables age, sex, and BMI remained in the model.
The frequency of the PAX-1 rs6137473 and rs169311 SNPs was in HWE. There was a significant difference in the frequency distribution of both polymorphisms comparing AIS cases and controls [Figure 3]. After adjustment for confounding factors, the variant homozygous PAX-1 genotypes (rs6137473 GG and rs169311 AA) were associated with higher risk of developing AIS than patients with the wild-type genotype, since in the control group, the frequency of the variant genotypes was lower and null, respectively, compared with case group [Table 2].
|Figure 3: Allelic and genotypic distribution of the PAX-1 polymorphisms in adolescent idiopathic scoliosis cases and controls (n = 178). P value calculated by Chi-square test or Fisher's exact test, when necessary. PAX-1 - Paired box 1|
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|Table 2: Association analysis between the PAX-1 polymorphisms and adolescent idiopathic scoliosis development (n=178)|
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The presence of PAX-1 rs6137473 and rs169311 polymorphisms was also evaluated regarding the severity of the AIS attributed by the lumbar and sagittal modifier and the value of the curve angle. An approximately 5-fold increased risk was observed for the more severe scoliosis phenotype for patients who had the variant genotype rs6137473 GG compared to individuals with the wild-type genotype [Table 3]. Regarding the thoracic kyphosis measured from T5-T12, no significant difference was observed in the presence of both polymorphisms (rs6137473 and rs169311) in PAX-1 gene between the AIS cases that presented sagittal modifier normal compared to those with hyperkyphosis (data not shown). Only one case of scoliosis had thoracic hypokyphosis, which did not allow for comparison between subgroups.
|Table 3: Association analysis between the PAX-1 polymorphisms and scoliosis severity, considering the lumbar spine modifier of Lenke's classification (n=59)|
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| Discussion|| |
The PAX-1 SNPs (rs6137473 and rs169311) were associated with the susceptibility of AIS, and PAX-1 rs6137473 can significantly add the risk of AIS severity in patients classified as Lenke type I and II.
As far as we know, the present work is the first study to describe the frequency of PAX-1 rs6137473 and rs169311 SNPs in the Brazilian population, a notoriously admixed and heterogeneous population. The discrepancies between different studies involving the influence of genetic variations on the susceptibility to complex disease may be impacted by distinct allele frequencies and heterogeneity in the studied populations, besides variation on environmental backgrounds. Furthermore, to successfully replicate the association between PAX1 SNPs and the susceptibility of AIS in the mixed population, our study has distinct strengths. First, despite the small number of included patients, we selected only patients with surgical indication for the treatment of scoliosis, classified as Lenke I and II, with the view to homogenize the group of cases to assess the influence of genetic variation in PAX-1 gene with the development and severity of the disease. AIS patients were recruited from an orthopedic referral hospital that reflects real-life community for diagnosing and treating AIS in a developing country. Second, all control individuals were evaluated by experienced spine surgeons, excluding spine deformities in the control group. However, the small number of patients in the Lenke's classification groups and no family history data to evaluate the differences between familial and nonfamilial AIS cases were the main limitations of this study. Relatives of individuals with idiopathic scoliosis have a higher incidence of the disease than the general population.,
As observed in the present study, AIS Lenke type I is the most frequent type in literature. A study involving 606 patients with AIS observed that 51% of cases corresponded to Lenke type I and 20% Type II. Furthermore, most AIS cases were female and normal or low BMI according to previous studies.,,, Women have 5 and 10-fold higher risk than male to develop progressive deformity and most severe forms of the AIS, respectively.,,, In addition, patients with severe curves had significantly lower BMI and it is hypothesized that this association may be related to the pathogenesis of the disease.,,
Although the etiology of scoliosis is still unknown, extrinsic and intrinsic factors can be associated with the disease. Genetic factors significantly influence the determination of clinical, anatomical, and biomechanical characteristics of scoliosis., The association of PAX-1 SNPs with the development of AIS has been described recently in a meta-analysis involving GWAS studies that evaluated 7956 cases of scoliosis and 88,459 controls. Other previous GWAS work had already identified AIS susceptibility within putative enhancers of the PAX1. PAX1 is required for adequate formation of vertebral bodies and can regulate the transformation of the notochord in the intervertebral disc.
The rs6137473 (G > A) SNP, located downstream of the PAX-1 gene, was also associated with an increased risk of developing AIS in the Japanese, American, Chinese population, and now in the Brazilian population. A higher frequency of the PAX-1 rs6137473 GG genotype was observed in cases of AIS and in the group of patients with lumbar modifier B and C, conferring an increased risk of developing the disease and its severity. The risk of severe scoliosis was previously observed in a northern Chinese Han population, using the Peking Union Medical College (PUMC) classification, which stratifies into three phenotypic groups. This study was the first to associate SNPs in PAX-1 gene with the curve-type phenotype, however the PUMC classification is little used in clinical practice., It has been observed that the presence of PAX-1 rs6137473 SNP did not influence the difference in PAX-1 expression between the genotypic groups (GG, GA, and AA), after analysis of mRNA extracted from bilateral paravertebral muscles of 84 patients with AIS.
The PAX-1 rs169311 (A > C) SNP is within an active enhancer site and may affect the binding of transcription factors and the expression of the PAX-1 gene.,, Individuals with the PAX-1 rs169311 AA genotype showed a significant reduction in PAX-1 expression compared to the rs169311 CC genotype. The PAX-1 rs169311 SNP was already associated with an increased risk for the development of idiopathic scoliosis in Chinese women, after analyzing 2914 patients with scoliosis with a curve magnitude variation of 21.2°–62.7° of the Cobb angle. In the present study, the presence of the PAX-1 rs169311 A allele conferred a risk for the development of AIS, in accordance with what has already been observed in the Chinese population.
Despite the ancestral diversity, these results replicated the association observed in homogeneous populations, which supports the hypothesis that SNPs in PAX-1 gene may serve as a biomarker to track the risk of development and the severity of AIS. It is becoming increasingly important to build a database to better understand and identify risk factors associated with AIS development and progression. Thus, future studies with a larger number of patients, including less severe curves, are needed to validate the influence of SNPs in PAX-1 gene on disease progression.
| Conclusions|| |
PAX-1 SNPs (rs169311 and rs6137473) were associated with increased risk of developing AIS and curve severity. This study may contribute to the evaluation of the influence of the genetic component involved in the development and severity of the disease, to elucidate possible etiological mechanisms, and to suggest policies for the prevention, diagnosis, and treatment of AIS.
The authors thank for the technical support of the INTO scientific initiation students from the Research Laboratory of Pharmaceutical Sciences (https://lapesfuezo.wixsite.com/website) and staff of the Research Division from the National Institute of Traumatology and Orthopaedics (INTO). This work was supported by the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES and Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.
Financial support and sponsorship
This study was financially supported by the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES and Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]