Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

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...

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Published in:The Journal of clinical investigation 2013-11, Vol.123 (11), p.4909-4917
Main Authors: 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
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Age
Asian People - genetics
Base Sequence
Binding Sites - genetics
Biomedical research
Carbohydrate Sulfotransferases
Case-Control Studies
Chromosomes
Chromosomes, Human, Pair 10 - genetics
Cohort Studies
Degeneration
Female
Finland
Gene expression
Genetic Linkage
Genetic Predisposition to Disease
Genetic variation
Genome-Wide Association Study
Genomes
Genomics
Grants
Heterozygote
Humans
Intervertebral Disc Degeneration - enzymology
Intervertebral Disc Degeneration - genetics
Intervertebral Disc Degeneration - pathology
Lumbar Vertebrae
Male
Meta-analysis
Methods
MicroRNA
MicroRNAs - genetics
MicroRNAs - metabolism
Mutation
Nervous system
Physiological aspects
Polymorphism, Single Nucleotide
RNA, Messenger - genetics
RNA, Messenger - metabolism
Software
Studies
Sulfotransferases - genetics
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI69277