A key feature of inherited canine (CHD) and human hip dysplasia (developmental dysplasia of the hip, DDH) is hip joint laxity which results in hip instability, subluxation, and debilitating secondary osteoarthritis. We genotyped a cross breed pedigree of 159 resistant greyhounds and dysplastic Labrador retrievers and we narrowed the original QTL to two at 15.5-17 cM and 18.5-21 cM based on SNP genotyping {{PMID: 18261189}}. We discovered a 10 base-pair haplotype in intron 30 of fibrillin 2 at 20.3-20.5 Mb on CFA11 that segregated with hip dysplasia in Labrador retrievers and contributed to the Norberg angle, a measure of hip dysplasia, in 4 other breeds. We confirmed that the expression of fibrillin 2 in fibrous hip capsule was two fold lower in the mutant homozygotes compared to the wild type homozygotes and that the mutation was significantly associated with secondary hip osteoarthritis. However other genes are clearly contributing to the phenotype. We genotyped 556 Labradors retrievers and other breeds at 770 informative SNPs to reveal a strong association between SNP BICF2G630292769 at base 15,798,805 on CFA11 associated with hip dysplasia at a false discovery rate of <1%. We further identified a QTL for CHD in Labrador retrievers on CFA01 and 2 independent genome-wide screens in other dog breeds also revealed a QTL for CHD on CFA01. CFA01 contains the relaxin 2 gene among others associated with hip laxity in other studies. Our hypothesis is that fibrillin 2 and genes in QTL at 15.7-17Mb and 18.5-21 Mb on CFA11 influence hip development by interacting with genes on CFA01 and when mutated contribute to canine hip dysplasia. We propose: (1) To measure expression of fibrillin 2 in the round ligament of the femoral head and in the articular cartilage. (2) To identify SNPs in the 15 genes in the QTL on CFA11 (except fibrillin 2), test for association with CHD, sequence any genes associated with hip dysplasia and secondary osteoarthritis and measure its expression in hip joint tissues. (3) To identify SNPs within relaxin, relaxin receptors, estrogen, estrogen receptors, and insulin-like growth factor-2, all located on CFA01. If an association between any of the SNPs in these genes and CHD is found, we will sequence the associated gene for mutations and measure its expression in hip tissues. (4) To measure temporal expression of associated genes using mRNA isolated from hip joint capsule and round ligament biopsy samples collected arthroscopically at 2, 4 and 6 months of age from the hips of Labrador retrievers bred for susceptibility or resistance to hip dysplasia. We will relate the identified genes in defined biochemical pathways and examine tissue architecture. In two years, we will have identified the genes associated with fibrillin 2 that contribute to CHD and may also inform human hip development and secondary hip osteoarthritis.
Congenital or developmental hip dysplasia occurs with a frequency of 1 to 18 per 1,000 live births. Dysplastic hips develop arthritis and it is estimated that up to 40% of hip arthritis in adults is due to hip dysplasia in childhood. Hip dysplasia has a genetic or familial predisposition. The medium to large dog commonly develops hip dysplasia and arthritis that mimics the human condition. Finding genes that contribute to canine hip dysplasia will eventually identify similar genes or physiological mechanisms that contribute to susceptibility to human hip dysplasia and arthritis. Such discoveries will lead to new preventions and treatments.
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