Evidence of association between GDF5 polymorphisms and congenital dislocation of the hip in a Caucasian population.

OBJECTIVE: Congenital dislocation of the hip (CDH) is a multifactorial disease which involves genetic factors that are still unidentified. Recently, a functional polymorphism (rs143383) of the 5'-untranslated region of GDF5 (Growth/Differentiation Factor 5) - previously reported to be associated with osteoarthritis - has been associated with CDH in a Chinese population. The aim of our study was to determine whether GDF5, known to be involved in bone, joint and cartilage morphogenesis, is also associated with CDH in Caucasians. DESIGN: We genotyped three tagSNPs (rs224334, rs143384, rs143383) in 239 cases and 239 controls from western Brittany (France) where CDH is frequent, and tested the association using both single-locus and haplotype-based approaches. RESULTS: The most significant association was observed with rs143384. The T allele of this SNP was overrepresented in cases (65.9% vs 55.9%, P=0.002). Under a recessive model, carriers of the TT genotype had a 1.71-fold higher risk of developing CDH than carriers of the other genotypes (OR(TT vs CT+CC)=1.71, 95% CI: [1.18-2.48], P=0.005). At a nominal level, the association was also significant with rs143383 (OR(TT vs CT+CC)=1.52, 95% CI: [1.05-2.19], P=0.026). The haplotype carrying the susceptibility alleles of these SNPs was also more frequent in cases (65.9% vs 55.9%, OR=1.53, 95% CI: [1.18-1.98], P=0.002). CONCLUSION: This study reports, for the first time, the association between GDF5 polymorphisms and CDH in Caucasians, and points out another polymorphism of interest that requires further investigation. Reduction in GDF5 expression might lead to developmental deficiency of ligaments and capsule in hip joint, and therefore contribute to CDH pathogenesis.

Do HOXB9 and COL1A1 genes play a role in congenital dislocation of the hip? Study in a Caucasian population.

OBJECTIVE: Congenital dislocation of the hip (CDH), which is one of the most common congenital skeletal disorders, corresponds to an abnormal seating of the femoral head in the acetabulum. It is commonly admitted that CDH presents a genetic component. However, little is known about the genetic factors involved. This study aimed to determine the role of two potential candidate genes on chromosome 17 in CDH: HOXB9 (involved in limb embryonic development) and COL1A1 (involved in joint laxity). METHOD: We set up a case-control association study (239 cases and 239 controls) in western Brittany (France) where CDH is particularly frequent. The set of informative single nucleotide polymorphisms (SNPs) in each gene was selected using Tagger and genotyped using the SNaPshot method (n=2 and n=10, respectively). The association was tested both through single-locus and haplotype-based analyses, using SAS and Haploview softwares. In addition, we carried out the transmission disequilibrium test (TDT) with the same polymorphisms from a sample of 81 trios (i.e., 81 patients included in the case-control study and their both parents). RESULTS: The case-control study revealed no significant association between CDH and the tagSNPs selected in both HOXB9 and COL1A1. Moreover, the TDT did not reveal distortion in allelic and haplotype transmission of the studied markers. CONCLUSION: Our study did not support an association between HOXB9 and COL1A1 and CDH in our population. These negative findings were obtained by population- and family-based designs. Analysis of the genetic component of CDH should focus on other candidate genes.