Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

You Qiang Song; Tatsuki Karasugi; Kenneth M.C. Cheung; Kazuhiro Chiba; Daniel W.H. Ho; Atsushi Miyake; Patrick Y.P. Kao; Kit Ling Sze; Anita Yee; Atsushi Takahashi; Yoshiharu Kawaguchi; Yasuo Mikami; Morio Matsumoto; Daisuke Togawa; Masahiro Kanayama; Dongquan Shi; Jin Dai; Qing Jiang; Chengai Wu; Wei Tian; Na Wang; John C.Y. Leong; Keith D.K. Luk; Shea Ping Yip; Stacey S. Cherny; Junwen Wang; Stefan Mundlos; Anthi Kelempisioti; Pasi J. Eskola; Minna Männikkö; Pirkka Mäkelä; Jaro Karppinen; Marjo Riitta Järvelin; Paul F. O'Reilly; Michiaki Kubo; Tomoatsu Kimura; Toshikazu Kubo; Yoshiaki Toyama; Hiroshi Mizuta; Kathryn S.E. Cheah; Tatsuhiko Tsunoda; Pak Chung Sham; Shiro Ikegawa; Danny Chan

doi:10.1172/JCI69277

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

You Qiang Song, Tatsuki Karasugi, Kenneth M.C. Cheung, Kazuhiro Chiba, Daniel W.H. Ho, Atsushi Miyake, Patrick Y.P. Kao, Kit Ling Sze, Anita Yee, Atsushi Takahashi, Yoshiharu Kawaguchi, Yasuo Mikami, Morio Matsumoto, Daisuke Togawa, Masahiro Kanayama, Dongquan Shi, Jin Dai, Qing Jiang, Chengai Wu, Wei TianNa Wang, John C.Y. Leong, Keith D.K. Luk, Shea Ping Yip, Stacey S. Cherny, Junwen Wang, Stefan Mundlos, Anthi Kelempisioti, Pasi J. Eskola, Minna Männikkö, Pirkka Mäkelä, Jaro Karppinen, Marjo Riitta Järvelin, Paul F. O'Reilly, Michiaki Kubo, Tomoatsu Kimura, Toshikazu Kubo, Yoshiaki Toyama, Hiroshi Mizuta, Kathryn S.E. Cheah, Tatsuhiko Tsunoda, Pak Chung Sham, Shiro Ikegawa, Danny Chan

Research output: Journal article publication › Journal article › Academic research › peer-review

102 Citations (Scopus)

Abstract

Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Original language	English
Pages (from-to)	4909-4917
Number of pages	9
Journal	Journal of Clinical Investigation
Volume	123
Issue number	11
DOIs	https://doi.org/10.1172/JCI69277
Publication status	Published - 1 Nov 2013

ASJC Scopus subject areas

General Medicine

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10.1172/JCI69277

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Song, Y. Q., Karasugi, T., Cheung, K. M. C., Chiba, K., Ho, D. W. H., Miyake, A., Kao, P. Y. P., Sze, K. L., Yee, A., Takahashi, A., Kawaguchi, Y., Mikami, Y., Matsumoto, M., Togawa, D., Kanayama, M., Shi, D., Dai, J., Jiang, Q., Wu, C., ... Chan, D. (2013). Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. Journal of Clinical Investigation, 123(11), 4909-4917. https://doi.org/10.1172/JCI69277

@article{031c8446501a42dda8212e8b75474ae7,

title = "Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant",

abstract = "Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.",

author = "Song, {You Qiang} and Tatsuki Karasugi and Cheung, {Kenneth M.C.} and Kazuhiro Chiba and Ho, {Daniel W.H.} and Atsushi Miyake and Kao, {Patrick Y.P.} and Sze, {Kit Ling} and Anita Yee and Atsushi Takahashi and Yoshiharu Kawaguchi and Yasuo Mikami and Morio Matsumoto and Daisuke Togawa and Masahiro Kanayama and Dongquan Shi and Jin Dai and Qing Jiang and Chengai Wu and Wei Tian and Na Wang and Leong, {John C.Y.} and Luk, {Keith D.K.} and Yip, {Shea Ping} and Cherny, {Stacey S.} and Junwen Wang and Stefan Mundlos and Anthi Kelempisioti and Eskola, {Pasi J.} and Minna M{\"a}nnikk{\"o} and Pirkka M{\"a}kel{\"a} and Jaro Karppinen and J{\"a}rvelin, {Marjo Riitta} and O'Reilly, {Paul F.} and Michiaki Kubo and Tomoatsu Kimura and Toshikazu Kubo and Yoshiaki Toyama and Hiroshi Mizuta and Cheah, {Kathryn S.E.} and Tatsuhiko Tsunoda and Sham, {Pak Chung} and Shiro Ikegawa and Danny Chan",

year = "2013",

month = nov,

day = "1",

doi = "10.1172/JCI69277",

language = "English",

volume = "123",

pages = "4909--4917",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "11",

}

Song, YQ, Karasugi, T, Cheung, KMC, Chiba, K, Ho, DWH, Miyake, A, Kao, PYP, Sze, KL, Yee, A, Takahashi, A, Kawaguchi, Y, Mikami, Y, Matsumoto, M, Togawa, D, Kanayama, M, Shi, D, Dai, J, Jiang, Q, Wu, C, Tian, W, Wang, N, Leong, JCY, Luk, KDK, Yip, SP, Cherny, SS, Wang, J, Mundlos, S, Kelempisioti, A, Eskola, PJ, Männikkö, M, Mäkelä, P, Karppinen, J, Järvelin, MR, O'Reilly, PF, Kubo, M, Kimura, T, Kubo, T, Toyama, Y, Mizuta, H, Cheah, KSE, Tsunoda, T, Sham, PC, Ikegawa, S & Chan, D 2013, 'Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant', Journal of Clinical Investigation, vol. 123, no. 11, pp. 4909-4917. https://doi.org/10.1172/JCI69277

TY - JOUR

T1 - Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

AU - Song, You Qiang

AU - Karasugi, Tatsuki

AU - Cheung, Kenneth M.C.

AU - Chiba, Kazuhiro

AU - Ho, Daniel W.H.

AU - Miyake, Atsushi

AU - Kao, Patrick Y.P.

AU - Sze, Kit Ling

AU - Yee, Anita

AU - Takahashi, Atsushi

AU - Kawaguchi, Yoshiharu

AU - Mikami, Yasuo

AU - Matsumoto, Morio

AU - Togawa, Daisuke

AU - Kanayama, Masahiro

AU - Shi, Dongquan

AU - Dai, Jin

AU - Jiang, Qing

AU - Wu, Chengai

AU - Tian, Wei

AU - Wang, Na

AU - Leong, John C.Y.

AU - Luk, Keith D.K.

AU - Yip, Shea Ping

AU - Cherny, Stacey S.

AU - Wang, Junwen

AU - Mundlos, Stefan

AU - Kelempisioti, Anthi

AU - Eskola, Pasi J.

AU - Männikkö, Minna

AU - Mäkelä, Pirkka

AU - Karppinen, Jaro

AU - Järvelin, Marjo Riitta

AU - O'Reilly, Paul F.

AU - Kubo, Michiaki

AU - Kimura, Tomoatsu

AU - Kubo, Toshikazu

AU - Toyama, Yoshiaki

AU - Mizuta, Hiroshi

AU - Cheah, Kathryn S.E.

AU - Tsunoda, Tatsuhiko

AU - Sham, Pak Chung

AU - Ikegawa, Shiro

AU - Chan, Danny

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

AB - Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

UR - http://www.scopus.com/inward/record.url?scp=84887462208&partnerID=8YFLogxK

U2 - 10.1172/JCI69277

DO - 10.1172/JCI69277

M3 - Journal article

SN - 0021-9738

VL - 123

SP - 4909

EP - 4917

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 11

ER -

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

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