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 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.
You-Qiang
YQ
Song
Tatsuki
T
Karasugi
Kenneth M C
KM
Cheung
Kazuhiro
K
Chiba
Daniel W H
DW
Ho
Atsushi
A
Miyake
Patrick Y P
PY
Kao
Kit Ling
KL
Sze
Anita
A
Yee
Atsushi
A
Takahashi
Yoshiharu
Y
Kawaguchi
Yasuo
Y
Mikami
Morio
M
Matsumoto
Daisuke
D
Togawa
Masahiro
M
Kanayama
Dongquan
D
Shi
Jin
J
Dai
Qing
Q
Jiang
Chengai
C
Wu
Wei
W
Tian
Na
N
Wang
John C Y
JC
Leong
Keith D K
KD
Luk
Shea-ping
SP
Yip
Stacey S
SS
Cherny
Junwen
J
Wang
Stefan
S
Mundlos
Anthi
A
Kelempisioti
Pasi J
PJ
Eskola
Minna
M
Männikkö
Pirkka
P
Mäkelä
Jaro
J
Karppinen
Marjo-Riitta
MR
Järvelin
Paul F
PF
O'Reilly
Michiaki
M
Kubo
Tomoatsu
T
Kimura
Toshikazu
T
Kubo
Yoshiaki
Y
Toyama
Hiroshi
H
Mizuta
Kathryn S E
KS
Cheah
Tatsuhiko
T
Tsunoda
Pak-Chung
PC
Sham
Shiro
S
Ikegawa
Danny
D
Chan
D020413:3' Untranslated Regions; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005387:Finland; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D055959:Intervertebral Disc Degeneration / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008159:Lumbar Vertebrae; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics*; D000097811:Carbohydrate Sulfotransferases
D020413:3' Untranslated Regions; D035683:MicroRNAs; D012333:RNA, Messenger; D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases; C546275:MIRN513A1 microRNA, human