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Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis.

ABSTRACT: To test whether single-nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape, and to determine whether FRZB variant alleles affect the relationship between hip shape and radiographic osteoarthritis (OA) of the hip.A nested case-control study of Caucasian women, age ?65 years, from the Study of Osteoporotic Fractures cohort was performed. Cases (n = 451) were defined as subjects with radiographic evidence of incident hip OA during followup, while controls (n = 601) were subjects in whom no radiographic hip OA was identified at baseline or followup. Statistical shape modeling (SSM) of the digitized hip radiographs was performed to assess the shape of the proximal femur, using 10 independent modes of shape variation generated by principal components analysis. In addition, center-edge angle and acetabular depth were assessed as geometric measurements of acetabular shape. The association of the rs288326 and rs7775 FRZB variant alleles with hip shape was analyzed using linear regression. The effect of these alleles on the relationship between hip shape and radiographic hip OA was analyzed using a logistic regression model with or without inclusion of interaction terms.The rs288326 and rs7775 alleles were associated with the shape of the proximal femur (SSM mode 2). There was a significant interaction between the rs288326 SNP and proximal femur shape (SSM mode 2) in predicting radiographic hip OA (P for interaction = 0.022). Among subjects with the rs288326 variant allele, there was an increased likelihood of radiographic hip OA in association with increasing quartiles of proximal femur shape mode 2 (for the fourth quartile of mode 2, odds ratio 2.5, 95% confidence interval 1.15, 5.25; P for linear trend = 0.02).The rs288326 and rs7775 FRZB SNPs are associated with the shape of the proximal femur. The presence of the rs288326 SNP alters the relationship between proximal femur shape and incident radiographic hip OA. These findings suggest that FRZB may serve an important role in determining hip shape and may modify the relationship between hip shape and OA.

SUBMITTER: Baker-Lepain JC

PROVIDER: S-EPMC3340442 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis.

Baker-Lepain Julie C JC Lynch John A JA Parimi Neeta N McCulloch Charles E CE Nevitt Michael C MC Corr Maripat M Lane Nancy E NE

Arthritis and rheumatism 20120501 5

<h4>Objective</h4>To test whether single-nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape, and to determine whether FRZB variant alleles affect the relationship between hip shape and radiographic osteoarthritis (OA) of the hip.<h4>Methods</h4>A nested case-control study of Caucasian women, age ≥65 years, from the Study of Osteoporotic Fractures cohort was performed. Cases (n = 451) were defined as subjects with radiographic evidence of incident hip OA during followu ...[more]

PMID: 22544526

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Project description:OBJECTIVE:GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data. METHODS:Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB. RESULTS:A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09-1.22]) (P=9.4x10(-7)), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P=0.016]) or absent (for OA of the hand [P=0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P=0.019). CONCLUSION:Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.

Project description:IntroductionOsteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes. Recently, we identified the bone morphogenetic protein (BMP) and wingless-type MMTV integration site (WNT) signaling antagonists Gremlin 1 (GREM1), frizzled-related protein (FRZB) and dickkopf 1 homolog (Xenopus laevis) (DKK1) as articular cartilage's natural brakes of hypertrophic differentiation. In this study, we investigated whether factors implicated in osteoarthritis or regulation of chondrocyte hypertrophy influence GREM1, FRZB and DKK1 expression levels.MethodsGREM1, FRZB and DKK1 mRNA levels were studied in articular cartilage from healthy preadolescents and healthy adults as well as in preserved and degrading osteoarthritic cartilage from the same osteoarthritic joint by quantitative PCR. Subsequently, we exposed human articular chondrocytes to WNT, BMP, IL-1β, Indian hedgehog, parathyroid hormone-related peptide, mechanical loading, different medium tonicities or distinct oxygen levels and investigated GREM1, FRZB and DKK1 expression levels using a time-course analysis.ResultsGREM1, FRZB and DKK1 mRNA expression were strongly decreased in osteoarthritis. Moreover, this downregulation is stronger in degrading cartilage compared with macroscopically preserved cartilage from the same osteoarthritic joint. WNT, BMP, IL-1β signaling and mechanical loading regulated GREM1, FRZB and DKK1 mRNA levels. Indian hedgehog, parathyroid hormone-related peptide and tonicity influenced the mRNA levels of at least one antagonist, while oxygen levels did not demonstrate any statistically significant effect. Interestingly, BMP and WNT signaling upregulated the expression of each other's antagonists.ConclusionsTogether, the current study demonstrates an inverse correlation between osteoarthritis and GREM1, FRZB and DKK1 gene expression in cartilage and provides insight into the underlying transcriptional regulation. Furthermore, we show that BMP and WNT signaling are linked in a negative feedback loop, which might prove essential in articular cartilage homeostasis by balancing BMP and WNT activity.

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Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis.

Publications

Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis.

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