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 Francis 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 Francis 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

Social Genetic & Developmental Psychiatry

Research output: Contribution to journal › Article › peer-review

105 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
Journal	The Journal of clinical investigation
Volume	123
Issue number	11
DOIs	https://doi.org/10.1172/JCI69277
Publication status	Published - 1 Nov 2013

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Song, Y.-Q., Karasugi, T., M.C. Cheung, K., Chiba, K., W.H. Ho, D., Miyake, A., Kao, P. Y. P., Ling Sze, K., 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. The Journal of clinical investigation, 123(11). https://doi.org/10.1172/JCI69277

@article{88ef60cea0ec4a48bd5fd9650f219b01,

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 = "You-Qiang Song and Tatsuki Karasugi and {M.C. Cheung}, Kenneth and Kazuhiro Chiba and {W.H. Ho}, Daniel and Atsushi Miyake and Kao, {Patrick Y.P.} and {Ling Sze}, Kit 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 {C.Y. Leong}, John and {D.K. Luk}, Keith and Shea-ping Yip and Cherny, {Stacey S.} and Junwen Wang and Stefan Mundlos and Anthi Kelempisioti and {J. Eskola}, Pasi and Minna M{\"a}nnikk{\"o} and Pirkka M{\"a}kel{\"a} and Jaro Karppinen and Marjo-Riitta J{\"a}rvelin and O'Reilly, {Paul Francis} and Michiaki Kubo and Tomoatsu Kimura and Toshikazu Kubo and Yoshiaki Toyama and Hiroshi Mizuta and Cheah, {Kathryn S.E.} and Tatsuhiko Tsunoda and Pak-Chung Sham and Shiro Ikegawa and Danny Chan",

year = "2013",

month = nov,

day = "1",

doi = "10.1172/JCI69277",

language = "English",

volume = "123",

journal = "The Journal of clinical investigation",

publisher = "The American Society for Clinical Investigation",

number = "11",

}

Song, Y-Q, Karasugi, T, M.C. Cheung, K, Chiba, K, W.H. Ho, D, Miyake, A, Kao, PYP, Ling Sze, K, 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, C.Y. Leong, J, D.K. Luk, K, Yip, S, Cherny, SS, Wang, J, Mundlos, S, Kelempisioti, A, J. Eskola, P, Männikkö, M, Mäkelä, P, Karppinen, J, Järvelin, M-R, O'Reilly, PF, Kubo, M, Kimura, T, Kubo, T, Toyama, Y, Mizuta, H, Cheah, KSE, Tsunoda, T, Sham, P-C, Ikegawa, S & Chan, D 2013, 'Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant', The Journal of clinical investigation, vol. 123, no. 11. 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 - M.C. Cheung, Kenneth

AU - Chiba, Kazuhiro

AU - W.H. Ho, Daniel

AU - Miyake, Atsushi

AU - Kao, Patrick Y.P.

AU - Ling Sze, Kit

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 - C.Y. Leong, John

AU - D.K. Luk, Keith

AU - Yip, Shea-ping

AU - Cherny, Stacey S.

AU - Wang, Junwen

AU - Mundlos, Stefan

AU - Kelempisioti, Anthi

AU - J. Eskola, Pasi

AU - Männikkö, Minna

AU - Mäkelä, Pirkka

AU - Karppinen, Jaro

AU - Järvelin, Marjo-Riitta

AU - O'Reilly, Paul Francis

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.

U2 - 10.1172/JCI69277

DO - 10.1172/JCI69277

M3 - Article

VL - 123

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

IS - 11

ER -

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Abstract

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