Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand

Abstract

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.

Figure 1

Forest plot of study-specific estimates and random-effects summary odds ratio (OR) estimates and 95% confidence intervals (95% CIs) for the association between the rs143383 polymorphism of the GDF5 gene and hip osteoarthritis (OA) (A), knee OA (B), and hand OA (C). Diamonds represent the point estimate (center of each diamond) and the 95% CIs (horizontal tips of each diamond). Dashed lines represent the summary OR estimate. Sizes of the shaded boxes represent the weight of each study. Asterisks indicate that the data are entirely new or expanded compared with what was included in a previous meta-analysis (12). GARP = Genetics, Osteoathritis, and Progression study.

Figure 2

Forest plot of study-specific estimates and random-effects summary OR estimates and 95% CIs for the association between the rs7775 polymorphism of the FRZB gene and hip OA (A), knee OA (B), and hand OA (C). Diamonds represent the point estimate (center of each diamond) and the 95% CIs (horizontal tips of each diamond). Dashed lines represent the summary OR estimate. Sizes of the shaded boxes represent the weight of each study. Asterisks indicate that the data are entirely new or expanded compared with what was included in a previous meta-analysis (18). SOF = Study of Osteoporotic Fractures (see Figure 1 for other definitions).

Figure 3

Forest plot of study-specific estimates and random-effects summary OR estimates and 95% CIs for the association between the rs288326 polymorphism of the FRZB gene and hip OA (A), knee OA (B), and hand OA (C). This polymorphism was not evaluated in a previous meta-analysis (18). Diamonds represent the point estimate (center of each diamond) and the 95% CIs (horizontal tips of each diamond). Dashed lines represent the summary OR estimate. Sizes of the shaded boxes represent the weight of each study. SOF = Study of Osteoporotic Fractures (see Figure 1 for other definitions).