Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts.
OBJECTIVE
To examine the association of genetic variation in key players in the Wnt signaling pathway with aspects of osteoarthritis (OA) in two population-based cohort studies: the Rotterdam Study and the Chingford Study.


METHODS
Radiographic OA (ROA) was defined as a Kellgren/Lawrence score (K/L) score > or = 2 for the knee and hip. Total hip replacement (THR) was scored. Hand OA was defined as presence of ROA (K/L > or = 2) in two out of three hand joint groups [distal interphalangeal (DIPs), proximal interphalangeal (PIPs), first carpometacarpal (CMC1)/trapezio-scaphoid joint (TS)] of each hand. The concentration of urinary C-terminal cross-linked telopeptide of type II collagen (CTX-II) was standardized to the total urine creatinine. Genotypes for the amino acid variants, Arg200Trp and Arg324Gly of Frizzled-Related protein gene (FRZB), Ala1330Val of Low-density lipoprotein receptor-related protein 5 (LRP5) and Ile1062Val of Low-density lipoprotein receptor-related protein 6 (LRP6), were obtained using the Taqman allelic discrimination assay. A meta-analysis was performed for the FRZB Arg324Gly polymorphism and hip- and knee-OA using RevMan version 4.3.


RESULTS
No consistent associations were observed between the FRZB, LRP5 and LRP6 amino acid variants and radiographic hip-, knee-, or hand-OA or THR, in either study population. While power was limited for most studies to date, a meta-analysis of all published studies regarding the FRZB Arg324Gly polymorphism was performed for hip- and knee-OA separately. This showed no significant associations between the Gly324 allele and risk for hip- or knee OA, although there was large heterogeneity between studies for hip OA in females.


CONCLUSIONS
No association was seen between FRZB, LRP5 and LRP6 variants with radiographic osteoarthritic outcomes in two population-based cohorts. In future studies, increased power and standardization of OA-phenotypes are highly recommended for replication studies and to allow meta-analysis.
Kerkhof
J M
JM
Department of Internal Medicine Erasmus Medical Center, Rotterdam, The Netherlands.
Uitterlinden
A G
AG
Valdes
A M
AM
Hart
D J
DJ
Rivadeneira
F
F
Jhamai
M
M
Hofman
A
A
Pols
H A P
HA
Bierma-Zeinstra
S M A
SM
Spector
T D
TD
van Meurs
J B
JB
D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007596:Joints / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011859:Radiography; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D000099274:Frizzled-Related Proteins
D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; D000099274:Frizzled-Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human