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

Abstract

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Figure 1. Flow chart of study subject selection

RHOA = radiographic hip osteoarthritis.

Figure 2. Hip shape measurements

(A) Outline of the proximal femur used in statistical shape modeling (SSM). A 60-point outline of the proximal femur between two anchor points (the inferior margin of lesser trochanter and the corresponding point on the lateral femoral shaft) was made (green dots), and coordinates of the points were entered into the SSM software to generate the 10 independent modes of hip shape variation by principal components analysis. The outline of the proximal femur generated by SSM is shown in yellow. (B) Illustration of variation in proximal femur shape in Mode 2. Mean shape of Mode 2 (green line) with ± 1 standard deviation (SD) (red and blue lines) is shown. (C and D) Acetabular measurements used in the study.

Figure 3. Schematic depicting possible interrelationships between FRZB, hip shape, and osteoarthritis

Solid arrows represent associations that have previously been reported, while dotted lines represent associations that are under investigation in this study.