Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada.
Program of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
Sci Rep. 2019 Apr 5;9(1):5712. doi: 10.1038/s41598-019-41191-4.
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 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 and coefficient = -9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 (P = 9.9 × 10 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 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.
脊柱畸形进展的细胞和分子机制在青少年特发性脊柱侧凸（AIS）中仍知之甚少。在这项研究中，纳入了 804 名法裔加拿大患者和 278 名年龄和性别匹配的对照者，并对几丁质酶 3 样蛋白 1（CHI3L1）基因或其启动子中的 12 个单核苷酸多态性（SNP）进行了基因分型。通过 ELISA 测定血浆 YKL-40 水平。我们表明，循环 YKL-40 水平的升高与脊柱畸形进展风险降低相关。我们还进一步确定了多个 CHI3L1 SNP 及其单倍型与血浆 YKL-40 水平和脊柱侧凸严重程度之间的显著关联，这些关联是根据它们在特定表型中的分类来确定的。在表型 FG3 组中，我们发现携带单倍型 G-G-A-G-G-A（rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261）的患者（占病例的 48%）与血浆 YKL-40 水平呈正相关（P=7.6×10 和系数=36）。相反，在分析对象中占 15%的单倍型 A-A-G-G-G-G 与血浆 YKL-40 水平呈强负相关（P=2×10 和系数=-9.56）。我们发现，这种单倍型与表型 FG2 中的 AIS 患者（P=9.9×10 和系数=-13.53）关联最强，与其他两种表型相比，这些患者更易发生严重的脊柱侧凸。值得注意的是，它在女性中的关联更强（P=1.6×10 和系数=-10.08），而在男性中较弱（P=0.0021 和系数=-9.01）。在功能水平上，我们表明 YKL-40 治疗可挽救原发性 AIS 成骨细胞中发生的 Gi 偶联受体信号功能障碍。总的来说，我们的研究结果揭示了 YKL-40 在 AIS 发病机制中的新作用，以及一种新的分子机制干扰脊柱畸形的进展。
