Association between Common Variants near <em>LBX1</em> and Adolescent Idiopathic Scoliosis Replicated in the Chinese Han Population

<div><h3>Background</h3><p>Adolescent idiopathic scoliosis (AIS) is one of the most common spinal deformities found in adolescent populations. Recently, a genome-wide association study (GWAS) in a Japanese population indicated that three single nucleotide polymorphisms (SNPs), rs11190870, rs625039 and rs11598564, all located near the <em>LBX1</em> gene, may be associated with AIS susceptibility <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053234#pone.0053234-Takahashi1">[1]</a>. This study suggests a novel AIS predisposition candidate gene and supports the hypothesis that somatosensory functional disorders could contribute to the pathogenesis of AIS. These findings warrant replication in other populations.</p> <h3>Methodology/Principal Findings</h3><p>First, we conducted a case-control study consisting of 953 Chinese Han individuals from southern China (513 patients and 440 healthy controls), and the three SNPs were all found to be associated with AIS predisposition. The ORs were observed as 1.49 (95% CI 1.23–1.80, <em>P</em> = 5.09E-5), 1.70 (95% CI 1.42–2.04, <em>P</em> = 1.17E-8) and 1.52 (95% CI 1.27–1.83, <em>P</em> = 5.54E-6) for rs625039, rs11190870 and rs11598564, respectively. Second, a case-only study including a subgroup of AIS patients (N = 234) was performed to determine the effects of these variants on the severity of the condition. However, we did not find any association between these variants and the severity of curvature.</p> <h3>Conclusion</h3><p>This study shows that the genetic variants near the <em>LBX1</em> gene are associated with AIS susceptibility in Chinese Han population. It successfully replicates the results of the GWAS, which was performed in a Japanese population.</p> </div

6 tag SNPs selected for the association study.

<p>6 tag SNPs selected for the association study.</p

Gene expression levels in response to different doses of leptin.

<p>The expression levels in control group without leptin treatment were used as calibrators. Relative expression levels were calculated by using the 2^−ΔΔCt method.</p

Linkage disequilibrium (LD) pattern and Haplotypes of the <i>Leptin</i> gene from the 45 healthy subjects.

<p>Two LD blocks were identified in the sequenced genomic region of the gene (calculated with the Solid spine of LD algorithm with the Minor Allele Frequency≥1%). Arrows indicate the positions of the 6 tag SNPs selected for the association study.</p

Association between the SNPs and AIS predisposition, stratified by sex.

a<p>Risk allele frequency (RAF).</p>b<p>Allelic odds ratio.</p>c<p>Confidence interval (CI).</p>d<p><i>P</i>-values were adjusted using the Bonferroni method for multiple tests.</p>e<p><i>P</i> -values were calculated using the Cochran-Armitage trend test.</p>f<p><i>P</i> -values were calculated using the χ² test.</p

Association between age and genotype.

a<p><i>P</i>-values were calculated using Kruskal–Wallis test.</p

The expression of leptin receptor in induced adipocytes was determined by immunocytochemistry.

<p>The AIS MSCs (a) was from a 14-year-old boy (Cobb angle = 80°) and the normal control (b) was from a 19-year-old boy. Note that the leptin receptors were abundant in undifferentiated MSCs from control sample, but were rare in those from AIS sample. Scale bar = 200 µm.</p

Gene expression levels in response to different doses of leptin.

<p>The expression levels in control group without leptin treatment were used as calibrators. Relative expression levels were calculated by using the 2^−ΔΔCt method.</p

Summary of the AIS and control subjects in cytological study.

*<p><i>P</i><0.05 was considered statistically significant.</p>**<p><i>P</i><0.01.</p

Summary of the AIS and control subjects in genetic association study.

*<p><i>P</i><0.05 was considered statistically significant.</p>**<p><i>P</i><0.01.</p