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: Contribution to journalArticle

52 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 languageEnglish
Pages (from-to)4909-4917
Number of pages9
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
Publication statusPublished - 2013 Nov 1

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Intervertebral Disc Degeneration
MicroRNAs
Alleles
Intervertebral Disc
Proteoglycans
Genome
Messenger RNA
Genes
Meta-Analysis
carbohydrate sulfotransferases
Binding Sites
Water
Enzymes
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Song, Y. Q., Karasugi, T., Cheung, K. M. C., Chiba, K., Ho, D. W. H., Miyake, A., ... 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

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. / Song, You Qiang; Karasugi, Tatsuki; Cheung, Kenneth M C; Chiba, Kazuhiro; Ho, Daniel W H; Miyake, Atsushi; Kao, Patrick Y P; Sze, Kit Ling; Yee, Anita; Takahashi, Atsushi; Kawaguchi, Yoshiharu; Mikami, Yasuo; Matsumoto, Morio; Togawa, Daisuke; Kanayama, Masahiro; Shi, Dongquan; Dai, Jin; Jiang, Qing; Wu, Chengai; Tian, Wei; Wang, Na; Leong, John C Y; Luk, Keith D K; Yip, Shea Ping; Cherny, Stacey S.; Wang, Junwen; Mundlos, Stefan; Kelempisioti, Anthi; Eskola, Pasi J.; Männikkö, Minna; Mäkelä, Pirkka; Karppinen, Jaro; Järvelin, Marjo Riitta; O'Reilly, Paul F.; Kubo, Michiaki; Kimura, Tomoatsu; Kubo, Toshikazu; Toyama, Yoshiaki; Mizuta, Hiroshi; Cheah, Kathryn S E; Tsunoda, Tatsuhiko; Sham, Pak Chung; Ikegawa, Shiro; Chan, Danny.

In: Journal of Clinical Investigation, Vol. 123, No. 11, 01.11.2013, p. 4909-4917.

Research output: Contribution to journalArticle

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
Song YQ, Karasugi T, Cheung KMC, Chiba K, Ho DWH, Miyake A et al. Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. Journal of Clinical Investigation. 2013 Nov 1;123(11):4909-4917. https://doi.org/10.1172/JCI69277
Song, You Qiang ; Karasugi, Tatsuki ; Cheung, Kenneth M C ; Chiba, Kazuhiro ; Ho, Daniel W H ; Miyake, Atsushi ; Kao, Patrick Y P ; Sze, Kit Ling ; Yee, Anita ; Takahashi, Atsushi ; Kawaguchi, Yoshiharu ; Mikami, Yasuo ; Matsumoto, Morio ; Togawa, Daisuke ; Kanayama, Masahiro ; Shi, Dongquan ; Dai, Jin ; Jiang, Qing ; Wu, Chengai ; Tian, Wei ; Wang, Na ; Leong, John C Y ; Luk, Keith D K ; Yip, Shea Ping ; Cherny, Stacey S. ; Wang, Junwen ; Mundlos, Stefan ; Kelempisioti, Anthi ; Eskola, Pasi J. ; Männikkö, Minna ; Mäkelä, Pirkka ; Karppinen, Jaro ; Järvelin, Marjo Riitta ; O'Reilly, Paul F. ; Kubo, Michiaki ; Kimura, Tomoatsu ; Kubo, Toshikazu ; Toyama, Yoshiaki ; Mizuta, Hiroshi ; Cheah, Kathryn S E ; Tsunoda, Tatsuhiko ; Sham, Pak Chung ; Ikegawa, Shiro ; Chan, Danny. / Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 11. pp. 4909-4917.
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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.",
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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

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