Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

• Published in: The Journal of clinical investigation Vol. 123; no. 11; pp. 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: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.11.2013
• 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; Finland; Japan; China
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI69277

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.