Table 2.
The reported SNPs with statistically significant evidence in AIS curve progression (NS = non-specified, OR = odds ratio).
| Gene | SNP Risk Allele | Molecular Pathway | Sensitivity/Specificity/OR/CI | p-Value | Results | Reference |
|---|---|---|---|---|---|---|
| ER1 (estrogen receptor 1) | XbaI site (A/G rs934099)–Genotype Xx | Estrogen determines different skeletal and sexual growth reactions that are genetically determined by the ER gene polymorphism | NS | 0.03 | The mean (±SD) initial Cobb angle was 27.5 ± 14.8 with genotype XX, 26.2 ± 9.9 with genotype Xx, and 23.3 ± 8.5 with genotype xx, and the differences were statistically significant. XbaJ polymorphism in the ER gene was significantly associated with curve progression. |
M. Inoue (2002) |
| ER1 (estrogen receptor) | PvuLL site (rs2234693) | Estrogen determines different skeletal and sexual growth reactions that are genetically determined by the ER gene polymorphism | Sensitivity: 28–69% Specificity: 44–82% Positive predictive value: 45–51% Negative predictive value: 63–68% |
0.0128 | A significant difference was shown between cases (Cobb angle >40°) and controls in the polymorphic distribution of the rs2234693 (Pvu II) site in the ER 1 gene (P 0.0128). In addition, the frequency of the -16C allele in the cases (73.3%) was less than in the controls (81.5%). | D. Zhao (2009) |
| ERalpha (Estrogen receptor alpha) | rs9340799-GA and G allele | Estrogen determines different skeletal and sexual growth reactions that are genetically determined by the ER gene polymorphism | Sensitivity: 51% Specificity: 82% OR = 3.559 within 95% Confidence Interval (CI): 0.99–4.38 |
<0.001 | Statistically significant differences between the two groups (progression vs. non-progression) in SNP rs9340799 in ERa (genotype GA (50.9 vs. 17.9) and G allele (27.1 vs. 12.0%). Allele G of ER alpha could be considered as risk factor leading to progression of AIS curve. |
L. Xu (2011) |
| CALM1 (Calmodulin 1 gene) | rs12885713 | Calmodulin regulates the contractile properties of muscles and platelets through its interaction with actin and myosin and regulates cellular calcium through transport across the cell membrane | Sensitivity: 28–69% Specificity: 44–82% Positive predictive value: 45–51% Negative predictive value 63–68% |
0.034 | A significant association was found between double curve and polymorphic distributions of CALM 1 SNPs (0.034). A combination of CALM1 and ER1 gene polymorphisms might be related to double curve in patients with AIS, which is associated with curve progression. | D. Zhao (2009) |
| IL-17RC (Interleukin 17 receptor) | Rs708567-genotype GG | The IL-17R complex mediates the signal transduction of the IL-17 signaling axis. This promotes the production of pro-inflammatory cytokines. | Sensitivity: 94% Specificity: 17% Positive predictive value: 60% Negative predictive value: 69% |
0.007 | Overall, AIS patients with the GG genotype showed a significantly higher mean maximum Cobb angle (36.01° ± 13.12°, 20°–58°) than those with the AG genotype (28.92° ± 7.43°, range 20°–51°, p = 0.007). | S. Zhou (2012) |
| IGF-1 (Insuline growth factor–1) | rs5742612-TT genotype | IGF-I has a pivotal role in bone growth determining different skeletal growth | Sensitivity: 88% Specificity: 22% Positive predictive value: 57% Negative predictive value: 61% |
0.04 | Cobb’s angle is higher in patients with TT genotype (Mean Cobb’s angle: 38.1° in TT vs. 35.9° in TC vs. 33.2° in CC group). | Y. Yeung (2006) |
| IGF-1 (Insuline growth factor–1) | rs5742612-GG genotype | IGF-I has a pivotal role in bone growth determining different skeletal growth | NS | 0.01 | IGF1polymorphism rs5742612 significantly differs among controls, high-risk, and low-risk groups. | S. Moon (2013) |
| MATN-1 (Matrillin 1) | rs1149048-allele G | Matrilin-1 is secreted primarily by chondrocytes and has a role in the assembly of cartilage. It has been confirmed that matrilin-1 has an important function in the organization of chondrocyte into distinct zones of growth plate. Disturbance of the chondrocyte zonal distribution could lead to musculoskeletal disorders, such as scoliosis. | OR = 1.35 within 95% confidence interval (CI): 1.14–1.61 |
0.02 | The mean maximal Cobb angle of patients with Rs1149048 SNPs is genotype GG: 37.91 ± 17.081, Genotype AA: 33.88 ± 14.681, Genotype AG: 32.25 ± 12. 421. Genotype GG develop a larger Cobb angle than those with genotype AA with a statistically significant difference. The tagSNP rs1149048 polymorphism in the MATN1 promoter region is associated with both susceptibility and disease progression in AIS. |
Z. Chen (2009) |
| TPH-1 (Trypophan hydroxylase 1) | rs10488682-Genotype AT and A allele | Tryptophan hydroxylases catalyze the biopterin-dependent monooxygenation of tryptophan to 5- hydroxytryptophan to (5-HTP), which is subsequently decarboxylated to form the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). It is the rate-limiting enzyme in the biosynthesis of serotonin. | Sensitivity: 51% Specificity: 82% OR = 2.289 within 95% Confidence Interval (CI): 1.18–4.43 |
0.002 0.033 |
Statistically significant differences between the two groups (progression vs. non-progression) in SNP rs10488682 in THP-1: genotype AT (33.3 vs. 13.0%), allele A (16.7 vs. 9.6%). Allele A of THP-1 could be considered a risk factor leading to progression of AIS curve. |
L. Xu (2011) |
| NFT3 (Neurothropin 3) | rs11063714-AA genotype | Scoliosis has developed in mice with NTF3 deficiency in previous studies. Increased expression of NTF3 mRNA was detected in the paravertebral muscle in AIS. |
Sensitivity: 43% Specificity: 82% Positive predictive value: 56% Negative predictive value: 72% |
<0.05 | For rs11063714 SNP, AIS patients with AA genotype had a significantly lower mean maximum Cobb angle than the patients with AG or GG genotypes, respectively: 25.45 ± 8.69 vs. 32.32 ± 13.36 vs. 34.26 ± 17.41. For rs11063714 SNP, there was a significantly higher successful ratio of brace treatment in AA genotype compared to GG genotype, respectively: 81.6% vs. 57.7%. |
Y. Qiu (2012) |
| LBX1 (Ladybird homebox 1) | rs11190870-TT genotype | LBX1 has an important role in developmental processes. This gene is expressed in the central nervous system and skeletal muscle | OR = 1.51 within 95% Confidence interval (CI): 1.33–1.71 |
<0.001 | AIS patients with TT genotype of rs11190870 had a larger Cobb angle than those with TC or CC genotype (50.8% vs. 25%; p < 0.001) |
H. Jiang (2013) |
| TGFB1 (transforming growth factor beta 1) |
Rs1800469 Rs1800471 |
TGFβ-1 protein triggers chemical signals that regulate various cell activities inside the cell, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis) | OR = 3.78 within 95% Confidence interval (CI): 1.42–10.05 |
0.038 | Kruskal–Wallis analysis of variance revealed the relationship between the SNP C-509T of the TGFB1 gene and the curve severity in females with AIS (Kruskal–Wallis statistic = 6.50) |
I. Ryzhkov (2013) |
| LAPTM4B (Lysosomal-associated transmembrane protein 4 beta) | rs2449539 | LAPTM4B is required for optimal lysosomal function. It blocks EGF-stimulated EGFR intraluminal sorting and degradation. Conversely, by binding with the phosphatidylinositol 4,5-bisphosphate, it regulates its PIP5K1C interaction, inhibits HGS ubiquitination, and relieves LAPTM4B inhibition of EGFR degradation | NS | 0.014 | LAPTM4B (lysosomal-associated transmembrane protein 4β) polymorphism rs2449539 significantly differs among the lower and high-risk groups. TT genotype most frequent in high-risk group and TC genotype in control group. | S. Moon (2013) |
| FNB1/2 (Fibrillin 1 and 2) | Rage damaging variants | Fibrillin mutations are the main mutated protein causing Marfan syndrome. This mutation usually interferes with the assembly of microfibrils resulting in a dominant, negative mechanism. | OR = 3.5 within 95% Confidence interval (CI): 1.6–7.3 |
0.026 | The average spinal curve in AIS cases with a rare FBN1 or FBN2 variant was 50.58°, compared with 42.18° in cases with no fibrillin variant. This indicates that FBN1 and FBN2 variants could serve as prognostic genetic markers to predict scoliosis progression. |
J Buchan (2014) |
| FNB1 (Fibrillin 1) | 106 SNPs studied | Fibrillin mutations are the main mutated protein causing Marfan syndrome. This mutation usually interferes with the assembly of microfibrils resulting in a dominant, negative mechanism. | OR = 1.78 within 95% Confidence interval (CI): 0.59–2.53 |
0.02 | The decreased expression level of FBN1 was remarkably correlated with the curve severity. The functional role of FBN1 in the progression of the AIS is worthy of further investigation. | F. Sheng (2018) |
| BCN 2 (Basonuclein 2) | rs10738445-Genotype CC | This gene encodes a conserved zinc finger protein. The encoded protein functions in skin color saturation. Mutations in this gene are associated with facial pigmented spots. This gene is also associated with susceptibility to adolescent idiopathic scoliosis | OR = 1.24 within 95% Confidence interval (CI): 1.01–1.54 |
0.01 | AIS patients were found to have significantly higher expression of the BNC2 as compared to controls. Moreover, AIS patients with genotype CC have larger Cobb angle than those with genotype TT (41.3 ± 13.5 vs. 35.4 ± 14.1). | L. Xu (2017) |
| TIMP2 (Tissue inhibitor of metalloproteinase 2) | rs2277700, rs11077401, rs2376999, and rs4789934 | The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMP), a group of peptidases involved in degradation of the extracellular matrix. | rs2277700-allele G: OR = 0.34 within 95%, Confidence interval (CI):0.16–0.74 rs11077401-allele T: OR = 0.13 within 95%, Confidence interval (CI):0.05–0.31 rs2376999-allele T OR = 0.37, Confidence interval (CI): 0.15–0.99 Rs478934-allele T OR = 0.21, Confidence Interval (CI): 0.04–1 |
rs2277700-allele G: <0.01 rs11077401-allele T: <0.01 rs2376999-allele T: =0.04 Rs478934-allele T: =0.048 |
Four of the polymorphisms (rs2277700, rs11077401, rs2376999, and rs4789934) showed non-equal distributions either in genotype or/and allele distributions in the patients of different progression rates. | M. Andrusiewicz (2019) |
| SOX9 (SRY-box transcription factor 9 SOX9) | rs12946942-recessive allele | It is expressed by proliferating, but not hypertrophic chondrocytes, which is essential for the differentiation of precursor cells into chondrocytes | OR = 1.36 within 95% Confidence Interval (CI): 1.25–1.49 |
<0.01 | The recessive allele of rs12946942 SNP showed significant association in severe AIS patients. | K. Takeda (2019) |
| CHD7 (chromodomain helicase DNA binding protein 7) | rs1017861-GG and AA alleles | CHD7 is essential for the formation of multipotent migratory neural crest and their ability to migrate throughout the body. | Rs1017861 GG: OR = 3.3 within 95% Confidence Interval (CI): 0.9–12.7 Rs1017861 AA: OR = 0.4 within 95% Confidence Interval (CI): 0.2–0.6 |
Rs1017861 GG: 0.0001 Rs1017861 AA: 0.002 |
Two polymorphisms, rs1017861 and rs4738813, were associated with curve severity and progression rate. | K. Borysiak (2020) |
| MIR4300 (microRNA4300 gene) | Rs1828853 | MIR4300HG is highly expressed in spinal cord, brain, skeletal muscle, salivary gland, and epithelial cells in various tissues and sperm | OR = 1.56 within 95% Confidence Interval (CI):1.35–1.80 |
<0.001 | MIR4300 host gene SNP rs1828853 showed association with progression of AIS. | Y. Ogura (2017) |
| MIR4300 HG (microRna 4300 gene) | rs35333564-allele G | RNAs are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs |
rs35333564-allele G: OR = 1.339 within 95% Confidence interval (CI): 1.07–1.67 |
0.01 |
Significant difference between two groups regarding both genotype frequency (3.1% vs. 1.3%, p = 0.025) and minor allele frequency (17.5% vs. 13.7%, p = 0.011) of rs35333564 in MIR4300 gene. |
Y. Wang (2021) |