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A Replication Study for Association of 5 Single Nucleotide Polymorphisms With Curve Progression of Adolescent Idiopathic Scoliosis in Japanese Patients

Ogura, Yoji MD*,†; Takahashi, Yohei MD, PhD*,†; Kou, Ikuyo PhD*; Nakajima, Masahiro MS*; Kono, Katsuki MD; Kawakami, Noriaki MD, DMSc§; Uno, Koki MD; Ito, Manabu MD, PhD[BULLET OPERATOR]; Minami, Shohei MD, PhD**; Yanagida, Haruhisa MD††; Taneichi, Hiroshi MD‡‡; Yonezawa, Ikuho MD§§; Tsuji, Taichi MD§; Suzuki, Teppei MD; Sudo, Hideki MD[BULLET OPERATOR]; Kotani, Toshiaki MD, PhD**; Watanabe, Kota MD, PhD; Chiba, Kazuhiro MD, PhD; Toyama, Yoshiaki MD, PhD; Matsumoto, Morio MD, PhD; Ikegawa, Shiro MD, PhD*

doi: 10.1097/BRS.0b013e3182761535

Study Design. A genetic association study of single nucleotide polymorphisms (SNPs) previously reported to be associated with curve progression of adolescent idiopathic scoliosis (AIS).

Objective. To determine whether the association of 5 SNPs with curve progression reported in Chinese with AIS are replicated in Japanese patients with AIS.

Summary of Background Data. AIS is a common spinal deformity and has a strong genetic predisposition. Predicting curve progression is important in clinical practice. The progression of AIS is reported to be associated with a number of genes. Associations with neurotrophin 3, G protein-coupled estrogen receptor, and tissue inhibitor of metalloproteinase 2 have been reported in Han Chinese with AIS; however, there has been no replication study for them.

Methods. We recruited 2117 patients with AIS with a Cobb angle of 10° or greater of scoliosis curves. They were grouped into progression and nonprogression groups according to their scoliosis curves. Patients whose scoliotic curves were 40° or greater were included in the progression group, and those whose scoliotic curves were less than 30° and had reached skeletal maturation in the nonprogression group. We evaluated the association of 5 SNPs (rs11063714 in neurotrophin 3, rs3808351, rs10269151, and rs4266553 in G protein-coupled estrogen receptor, and rs8179090 in tissue inhibitor of metalloproteinase 2 with curve progression by comparing risk allele frequencies between the 2 groups and the mean Cobb angle for each genotype.

Results. We evaluated the progression (N = 880) and nonprogression (N = 492) subjects, and their risk allele frequencies were not significantly different. The mean Cobb angle for each genotype also did not have statistical difference. We found no replication of the association on AIS curve progression in any of the SNPs.

Conclusion. The associations of the 5 SNPs with progression of AIS curve are not definite. Large-scale association studies based on appropriate criteria for progression would be necessary to identify SNPs associated with the curve progression.

Adolescent idiopathic scoliosis (AIS) has a strong genetic predisposition, and a number of single nucleotide polymorphisms (SNPs) were reported to have association with curve progression. We investigated the associations of 5 SNPs with AIS curve progression previously reported in Chinese AIS; however, they were not replicated in Japanese AIS.

*Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo, Japan

Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan

Department of Orthopaedic Surgery, Eiju General Hospital, Tokyo, Japan

§Department of Orthopaedic Surgery, Meijo Hospital, Nagoya, Japan

Department of Orthopaedic Surgery, National Hospital Organization, Kobe Medical Center, Kobe, Japan

[BULLET OPERATOR]Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University Graduate School of Medicine, Sapporo, Japan

**Department of Orthopaedic Surgery, Seirei Sakura Citizen Hospital, Sakura, Japan

††Department of Orthopaedic Surgery, Fukuoka Children's Hospital, Fukuoka, Japan

‡‡Department of Orthopaedic Surgery, Dokkyo Medical University School of Medicine, Mibu, Japan; and

§§Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Address correspondence and reprint requests to Shiro Ikegawa, MD, PhD, Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, 4-6-1 Sirokanedai, Minato-ku, Tokyo 108-8639, Japan; E-mail:

Acknowledgment date: July 27, 2012. First revision date: September 11, 2012. Acceptance date: September 23, 2012.

The manuscript submitted does not contain information about medical device(s)/drug(s).

The Grant-in-Aid for Scientific Research B (24390357) and Keio Gijuku Academic Development funds were received to support this work. Relevant financial activities outside the submitted work: consultancy.

© 2013 Lippincott Williams & Wilkins, Inc.