Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis.
Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 x 10(-4), Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 x 10(-4) -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.
Yang
Tie-Lin
TL
Key Laboratory of Biomedical Information Engineering of the Ministry of Education, Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Chen
Xiang-Ding
XD
Guo
Yan
Y
Lei
Shu-Feng
SF
Wang
Jin-Tang
JT
Zhou
Qi
Q
Pan
Feng
F
Chen
Yuan
Y
Zhang
Zhi-Xin
ZX
Dong
Shan-Shan
SS
Xu
Xiang-Hong
XH
Yan
Han
H
Liu
Xiaogang
X
Qiu
Chuan
C
Zhu
Xue-Zhen
XZ
Chen
Teng
T
Li
Meng
M
Zhang
Hong
H
Zhang
Liang
L
Drees
Betty M
BM
Hamilton
James J
JJ
Papasian
Christopher J
CJ
Recker
Robert R
RR
Song
Xiao-Ping
XP
Cheng
Jing
J
Deng
Hong-Wen
HW
D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D015519:Bone Density / Q000235:genetics; D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4; D004958:Estradiol / Q000097:blood; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D014453:Glucuronosyltransferase / Q000235:genetics*; D006620:Hip Fractures / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D010024:Osteoporosis / Q000235:genetics*; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D013739:Testosterone / Q000097:blood; D055815:Young Adult
D005819:Genetic Markers; D015778:Minor Histocompatibility Antigens; D013739:Testosterone; D004958:Estradiol; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human