Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee.
OBJECTIVE
To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA.


METHODS
Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately.


RESULTS
The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02).


CONCLUSIONS
Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.
Valdes
Ana M
AM
St. Thomas' Hospital, and King's College London, London, UK.
Loughlin
John
J
Oene
Mark Van
MV
Chapman
Kay
K
Surdulescu
Gabriela L
GL
Doherty
Michael
M
Spector
Tim D
TD
D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000208:ethnology; D064236:Cartilage Oligomeric Matrix Protein; D016022:Case-Control Studies; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007564:Japan / Q000453:epidemiology; D008297:Male; D064235:Matrilin Proteins; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000208:ethnology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D012737:Sex Factors; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000208:ethnology; D000099274:Frizzled-Related Proteins
D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D064235:Matrilin Proteins; D034041:Monomeric Clathrin Assembly Proteins; D000099274:Frizzled-Related Proteins; C439889:ASPN protein, human; C499177:COL2A1 protein, human; C439003:PICALM protein, human; C577553:TSP5 protein, human