Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis.
Susceptibility to osteoarthritis, the most common human arthritis, is known to be influenced by genetic factors. Through a genome-wide association study using approximately 100,000 SNPs, we have identified a previously unknown gene on chromosome 3p24.3, DVWA, which is associated with susceptibility to knee osteoarthritis. Expressed specifically in cartilage, DVWA encodes a 276-amino-acid protein with two regions corresponding to the von Willebrand factor type A domain (VWA domain). Several DVWA SNPs are significantly associated with knee osteoarthritis in two independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and a Han Chinese case-control cohort (combined P = 7.3 x 10(-11)). DVWA protein binds to beta-tubulin, and the binding is influenced by two highly associated missense SNPs (rs11718863 and rs7639618) located in the VWA domain. The Tyr169-Cys260 isoform of DVWA, which is overrepresented in knee osteoarthritis, showed weaker interaction. Our findings reveal a new paradigm for study of osteoarthritis etiology and pathogenesis.
Miyamoto
Yoshinari
Y
Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Shi
Dongquan
D
Nakajima
Masahiro
M
Ozaki
Kouichi
K
Sudo
Akihiro
A
Kotani
Akihiro
A
Uchida
Atsumasa
A
Tanaka
Toshihiro
T
Fukui
Naoshi
N
Tsunoda
Tatsuhiko
T
Takahashi
Atsushi
A
Nakamura
Yusuke
Y
Jiang
Qing
Q
Ikegawa
Shiro
S
D044466:Asian People / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D024142:Collagen Type VI; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D020370:Osteoarthritis, Knee / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D011544:Pseudogenes
C531065:COL6A4P1 protein, human; D024142:Collagen Type VI; D011506:Proteins