Genetic variant of COL11A2 gene is functionally associated with developmental dysplasia of the hip in Chinese Han population.

Renjie Xu,Yuxin Zhang,Junlan Lu,Xin Jiang,Ye Sun,Kexin Wang

doi:10.18632/aging.103040

Abstract

Objectives: Developmental dysplasia of the hip (DDH) is a common skeletal disorder. This study was conducted to demonstrate the association between DDH and a polymorphism rs9277935 of COL11A2 gene.Results: A significant difference in genotype distribution in a recessive model (TT+GT vs. GG) between two groups (P=0.017) was demonstrated. Analysis in female patients showed significantly greater frequency of minor allele G(0.49 vs. 0.43, p=0.024) and significantly higher distribution of GG genotype (p=0.006). DDH patients were found to have significantly lower COL11A2 expression than controls. Moreover, DDH patients with rs9277935 genotype TT have a significantly increased expression of COL11A2 than those with genotype GG. COL11A2 demonstrated chondrogenic properties in vitro.Conclusion: Polymorphism rs9277935 of gene COL11A2 is a functional variant regulating the expression and the chondrogenic properties of COL11A2 in DDH in Chinese Han population.Methods: A case-control candidate gene association study was conducted in 945 patients (350 radiologically confirmed DDH patients and 595 healthy controls). Difference of COL11A2 expression in hip joint tissue was compared between the patients and the controls. Allelic difference in Col11a2 expression by rs9277935 was assessed with luciferase activity. Chondrogenic effects of Col11a2 signaling on BMSCs were also determined in vitro.

Highlights

Developmental dysplasia of the hip (DDH) (OMIM# 142700) is a common congenital disease with both environmental and genetic components [1]
Patients with genotype TT were found to have a remarkably higher COL11A2 expression than those with genotype GG in both articular cartilage and joint ligament. (p = 0.02 for articular cartilage; p = 0.036 for joint ligament) Different COL11A2 expression was demonstrated in tissue sections of cartilage and ligament tissues in DDH patients with different genotypes for rs9277935 with immunofluorescent assay, showing significantly greater COL11A2 expression in patients with TT genotype compared to those with GG genotype. (Figure 2B)
To verify the allelic difference in Col11a2 expression by locus rs9277935 we tested the luciferase activity driven by different alleles. (Figure 3A) In comparison, it was apparent that T allele drove greater luciferase expression than G, with a 40% difference seen in ATDC5 (Figure 3A), indicating rs9277935 as a causative locus driving the luciferase expression change

Summary

Introduction

Developmental dysplasia of the hip (DDH) (OMIM# 142700) is a common congenital disease with both environmental and genetic components [1]. DDH patients present distinctively with hip joint laxity and skeletal dysplasia in the hip [2]. DDH is a hereditary progression [4,5,6], though mechanical factors (e.g. breech delivery, high birth weight, primiparity and oligoamnios) are suggested [7, 8]. Several DDH susceptibility genes (e.g. GDF5, TBX4, ASPN, PAPPA2 and TGFB1) were discovered by association www.aging-us.com study in Chinese and Caucasian populations [9,10,11,12,13]. A variety of environmental factors have been predicted to participate in DDH [16]. The complex etiology of DDH remains to be clarified

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