Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies.
OBJECTIVE
To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.


METHODS
A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.


RESULTS
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.


CONCLUSIONS
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
Cristina
C
Rodriguez-Fontenla
Manuel
M
Calaza
Evangelos
E
Evangelou
Ana M
AM
Valdes
Nigel
N
Arden
Francisco J
FJ
Blanco
Andrew
A
Carr
Kay
K
Chapman
Panos
P
Deloukas
Michael
M
Doherty
Tõnu
T
Esko
Carlos M
CM
Garcés Aletá
Juan J
JJ
Gomez-Reino Carnota
Hafdis
H
Helgadottir
Albert
A
Hofman
Ingileif
I
Jonsdottir
Hanneke J M
HJ
Kerkhof
Margreet
M
Kloppenburg
Andrew
A
McCaskie
Evangelia E
EE
Ntzani
William E R
WE
Ollier
Natividad
N
Oreiro
Kalliope
K
Panoutsopoulou
Stuart H
SH
Ralston
Yolande F
YF
Ramos
Jose A
JA
Riancho
Fernando
F
Rivadeneira
P Eline
PE
Slagboom
Unnur
U
Styrkarsdottir
Unnur
U
Thorsteinsdottir
Gudmar
G
Thorleifsson
Aspasia
A
Tsezou
André G
AG
Uitterlinden
Gillian A
GA
Wallis
J Mark
JM
Wilkinson
Guangju
G
Zhai
Yanyan
Y
Zhu
David T
DT
Felson
John P A
JP
Ioannidis
John
J
Loughlin
Andres
A
Metspalu
Ingrid
I
Meulenbelt
Kari
K
Stefansson
Joyce B
JB
van Meurs
Eleftheria
E
Zeggini
Timothy D
TD
Spector
Antonio
A
Gonzalez
D024161:Collagen Type XI / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D024161:Collagen Type XI; D042461:Vascular Endothelial Growth Factor A