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Study Design: A case-control association study.Objectives: To investigate the relationship between LBX1 (lady bird homeobox1) polymorphisms and adolescent idiopathic scoliosis (AIS) in French-Canadian population.Summary Of Background Data: It is widely accepted that genetic factors contribute to AIS. Although the LBX1 locus is so far the most successfully replicated locus in different AIS cohorts, these associations were replicated mainly in Asian populations, with few studies in Caucasian populations of European descent.Methods: We recruited 1568 participants (667 AIS patients and 901 healthy controls) in the French-Canadian population. Genomic data were generated using the Illumina Human Omni 2.5M BeadChip. An additional 121 AIS cases and 51 controls were genotyped for specific single-nucleotide polymorphisms (SNPs) by multiplex polymerase chain reaction using standard procedures. BEAGLE 3 was used to impute the following markers: rs7893223, rs11190878, and rs678741 against the 1000-genomes European cohort phased genotypes given that they were absent in our genome wide association studies (GWAS) panel. Resulting genotypes were combined then used for single marker and haplotyped-based association.Results: Four markers showed association with AIS in our cohort at this locus; rs11190870 the most studied marker, rs7893223, rs594791, and rs11190878. When we restricted the analysis to severe cases only, four additional SNPs showed associations: rs11598177, rs1322331, rs670206, and rs678741. In addition, we analyzed the associations of the observed haplotypes and dihaplotypes formed by these SNPs. The haplotype TTAAGAAA and its homozygous dihaplotype showed the highest association with our severe group and was the highest risk haplotype. The haplotype CCGCAGGG was significantly more associated with the control group, and its homozygous or heterozygous dihaplotype was less frequent in the severe group compared with the control group, suggesting that CCGCAGGG may represent a protective haplotype.Conclusion: We have replicated the association of the LBX1 locus with AIS in French-Canadian population, a novel European descent cohort, which is known for its unique genetic architecture.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Studies have revealed anthropometric discrepancies in girls with adolescent idiopathic scoliosis (AIS) compared to non-scoliotic subjects, such as a higher stature, lower weight, and lower body mass index. While the causes are still unknown, it was proposed that metabolic hormones could play a role in AIS pathophysiology. Our objectives were to evaluate the association of GLP1R A316T polymorphism in AIS susceptibility and to study its relationship with disease severity and progression. We performed a retrospective case-control association study with controls and AIS patients from an Italian and French Canadian cohort. The GLP1R rs10305492 polymorphism was genotyped in 1025 subjects (313 non-scoliotic controls and 712 AIS patients) using a validated TaqMan allelic discrimination assay. Associations were evaluated by odds ratio and 95% confidence intervals. In the AIS group, there was a higher frequency of the variant genotype A/G (4.2% vs. 1.3%, OR = 3.40, p = 0.016) and allele A (2.1% vs. 0.6%, OR = 3.35, p = 0.017) than controls. When the AIS group was stratified for severity (≤40° vs. >40°), progression of the disease (progressor vs. non-progressor), curve type, or body mass index, there was no statistically significant difference in the distribution of the polymorphism. Our results support that the GLP1R A316T polymorphism is associated with a higher risk of developing AIS, but without being associated with disease severity and progression.

The cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of spinal deformity progression risk. We further identified significant associations of multiple CHI3L1 SNPs and their haplotypes with plasma YKL-40 levels and scoliosis severity as a function of their classification in a specific endophenotype. In the endophenotype FG3 group, we found that patients harboring the haplotype G-G-A-G-G-A (rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261), which presented in 48% of the cases, showed a positive correlation with the plasma YKL-40 levels (P = 7.6 × 10 -6 and coefficient = 36). Conversely, the haplotype A-A-G-G-G-G, which presented in 15% of the analyzed subjects, showed a strong negative association with the plasma YKL-40 levels (P = 2 × 10 -9 and coefficient = -9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 (P = 9.9 × 10 -6 and coefficient = -13.53), who more often develop severe scoliosis compared to those classified in the other two endophenotypes. Of note, it showed stronger association in females (P = 1.6 × 10 -7 and coefficient = -10.08) than males (P = 0.0021 and coefficient = -9.01). At the functional level, we showed that YKL-40 treatments rescued Gi-coupled receptor signalling dysfunction occurring in primary AIS osteoblasts. Collectively, our findings reveal a novel role for YKL-40 in AIS pathogenesis and a new molecular mechanism interfering with spinal deformity progression.