Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population

Takahashi, Yohei; Matsumoto, Morio; Karasugi, Tatsuki; Watanabe, Kota; Chiba, Kazuhiro; Kawakami, Noriaki; Tsuji, Taichi; Uno, Koki; Suzuki, Teppei; Ito, Manabu; Sudo, Hideki; Minami, Shohei; Kotani, Toshiaki; Kono, Katsuki; Yanagida, Haruhisa; Taneichi, Hiroshi; Takahashi, Atsushi; Toyama, Yoshiaki; Ikegawa, Shiro

doi:10.1002/jor.21347

Cited by 60 publications

(46 citation statements)

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“…21 The associations of these two genes with scoliosis have not been replicated in the Japanese population. 30 In our study, we successfully replicated the previous GWAS finding that rs11190870 was highly significantly associated with AIS, which suggests that this SNP or the variants in linkage disequilibrium with this SNP may have an important role in the etiology of AIS. This is the first SNP associated with AIS that has been definitively replicated in another population.…”

Section: Discussionsupporting

confidence: 84%

SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese

et al. 2012

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A study was conducted to validate the most significant single nucleotide polymorphism (SNP) from a genome-wide association study of Japanese adolescent idiopathic scoliosis (AIS) patients in an independent southern Chinese population. In total, 300 AIS patients fulfilled the clinical criteria and 788 controls with MRI scans of the spine were included in the replication study. We employed case-control analysis to study the association of SNP rs11190870 near LBX1 (ladybird homeobox 1) with AIS in a southern Chinese population. The results suggest that SNP rs11190870 is significantly associated with AIS (P¼9.1Â10 À10 ; odds ratio¼1.85; 95% confidence interval¼1.52-2.25). The results of this study confirm that SNP rs11190870 is associated with AIS. Keywords: adolescent idiopathic scoliosis; replication study; rs11190870; southern Chinese INTRODUCTIONThe most common form of scoliosis is adolescent idiopathic scoliosis (AIS). AIS affects 1-4% of children aged between 10 and 16 years, 1,2 and affects more females than males. 3,4 It is known that the inheritance of AIS is complex. The role of genetic factors in scoliosis is well-documented and widely accepted. 5-8 Genome-wide linkage analyses have identified susceptibility loci on chromosome 6p, 8q12, 9q31.2-q34. 2, 10q, 12p, 17p11, 17q25.30-qtel, 18q, 19p13 and chromosome X. 9-16 Several candidate gene studies have also reported that genes such as COL1A1, COL1A2, FBN1, ESR, MATN1, MTNR1B, CHD7, VDR and GPER were associated with scoliosis. 10,[17][18][19][20][21][22][23][24] Recently, a genome-wide association study (GWAS) has been applied to identify the susceptibility loci of AIS. 25 The single nucleotide polymorphism (SNP) rs11190870 that is located in the 3¢-flanking region of LBX1 (ladybird homeobox 1) gene at chromosome 10q24.31 was identified as the most significant common variant in Japanese females with P¼1.24Â10 19 ; odds ratio (OR)¼1.56. 25 In the present study, we conducted a study to validate the association of rs11190870 with AIS in an independent southern Chinese population that contains 300 cases and 788 controls. Our results suggest that the SNP rs11190870 is highly significantly associated with AIS. MATERIALS AND METHODS SubjectsInformed consent was obtained from all individuals participating in this study. A cohort consisting of 300 AIS patients was recruited at the Duchess of Kent Children's Hospital in Hong Kong. The patient selection criteria for the study are as follows: (1) Patients with idiopathic scoliosis deformity involving the thoracic plus or minus the lumbar spine with Cobb's angles more than 35 degrees and required surgical operations in Duchess of Kent Children's Hospital. (2) The onset of scoliosis deformity was after 10 years and under 20 years of age. (3) Neuromuscular, congenital and syndromal scoliosis individuals were excluded by history taking, physical examination and X-ray of the spine. The control samples were from a large data set of southern Chinese population (3500 samples) recruited for a study on the genetics of degenera...

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Section: Discussionsupporting

confidence: 84%

SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese

et al. 2012

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“…A total of 2,142 AIS-affected subjects were recruited for the GWAS from ten collaborating hospitals (Japanese Scoliosis Clinical Research Group), according to the criteria previously described. 7,8,12 All underwent clinical and radiologic examinations by expert scoliosis surgeons. 11,144 control subjects for the GWAS were drawn from the BioBank Japan Project (see Web Resources) and its related projects, as previously described.…”

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confidence: 99%

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Ogura

Kou

Miura

et al. 2015

The American Journal of Human Genetics

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Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

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“…It is likely that this polymorphism could affect the gene expression of MT2, thus accounting for the lower mRNA expression level of MT2 found in AIS patients in the current study. The results of Qiu’s study could not be reproduced by a few related studies [53–56], which might partly be explained by the different ethnic populations [54–56] recruited for the studies. It is recognized that the ratio of combinations of the SNP of interest is different among different ethnic groups (Hapmap).…”

Section: Resultsmentioning

confidence: 75%

“…However, not all the AIS patients in this study showed a low expression of MT2, implying the heterogeneity of the disease and the presence of etiologies other than melatonin signaling dysfunction. The heterogeneous nature of AIS may also explain why associated common variants near melatonin receptor genes have not yet been identified in association studies [56]. …”

Section: Resultsmentioning

confidence: 99%

Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2

Yim

Yeung

Sun

et al. 2013

IJMS

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The defect of the melatonin signaling pathway has been proposed to be one of the key etiopathogenic factors in adolescent idiopathic scoliosis (AIS). A previous report showed that melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate whether the abnormal MT2 expression in AIS is quantitative or qualitative. Cultured osteoblasts were obtained from 41 AIS girls and nine normal controls. Semi-quantification of protein expression by Western blot and mRNA expression by TaqMan real-time PCR for both MT1 and MT2 were performed. Anthropometric parameters were also compared and correlated with the protein expression and mRNA expression of the receptors. The results showed significantly lower protein and mRNA expression of MT2 in AIS girls compared with that in normal controls (p = 0.02 and p = 0.019, respectively). No differences were found in the expression of MT1. When dichotomizing the AIS girls according to their MT2 expression, the group with low expression was found to have a significantly longer arm span (p = 0.036). The results of this study showed for the first time a quantitative change of MT2 in AIS that was also correlated with abnormal arm span as part of abnormal systemic skeletal growth.

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Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population

Cited by 60 publications

References 32 publications

SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese

SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2

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