Browsing by Subject "Hip dysplasia"

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  • Mikkola, Lea; Kyöstilä, Kaisa; Donner, Jonas; Lappalainen, Anu K.; Hytönen, Marjo K.; Lohi, Hannes; Iivanainen, Antti (2021)
    BackgroundCanine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants.ResultsWe execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Federation Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation.ConclusionsOur study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.
  • Mikkola, Lea; Kyöstilä, Kaisa; Donner, Jonas; Lappalainen, Anu K; Hytönen, Marjo K; Lohi, Hannes; Iivanainen, Antti (BioMed Central, 2021)
    Abstract Background Canine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants. Results We execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Fédération Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation. Conclusions Our study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.
  • Mikkola, Lea; Holopainen, Saila; Pessa-Morikawa, Tiina; Lappalainen, Anu K; Hytönen, Marjo K; Lohi, Hannes; Iivanainen, Antti (BioMed Central, 2019)
    Abstract Background Hip dysplasia and osteoarthritis continue to be prevalent problems in veterinary and human medicine. Canine hip dysplasia is particularly problematic as it massively affects several large-sized breeds and can cause a severe impairment of the quality of life. In Finland, the complex condition is categorized to five classes from normal to severe dysplasia, but the categorization includes several sub-traits: congruity of the joint, Norberg angle, subluxation degree of the joint, shape and depth of the acetabulum, and osteoarthritis. Hip dysplasia and osteoarthritis have been proposed to have separate genetic etiologies. Results Using Fédération Cynologique Internationale -standardized ventrodorsal radiographs, German shepherds were rigorously phenotyped for osteoarthritis, and for joint incongruity by Norberg angle and femoral head center position in relation to dorsal acetabular edge. The affected dogs were categorized into mild, moderate and severe dysplastic phenotypes using official hip scores. Three different genome-wide significant loci were uncovered. The strongest candidate genes for hip joint incongruity were noggin (NOG), a bone and joint developmental gene on chromosome 9, and nanos C2HC-type zinc finger 1 (NANOS1), a regulator of matrix metalloproteinase 14 (MMP14) on chromosome 28. Osteoarthritis mapped to a long intergenic region on chromosome 1, between genes encoding for NADPH oxidase 3 (NOX3), an intriguing candidate for articular cartilage degradation, and AT-rich interactive domain 1B (ARID1B) that has been previously linked to joint laxity. Conclusions Our findings highlight the complexity of canine hip dysplasia phenotypes. In particular, the results of this study point to the potential involvement of specific and partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderate-to-severe dysplasia and osteoarthritis of canine hip joints. Further studies should unravel the unique and common mechanisms for the various sub-traits.
  • Mikkola, Lea; Holopainen, Saila; Pessa-Morikawa, Tiina; Lappalainen, Anu K.; Hytönen, Marjo K.; Lohi, Hannes; Iivanainen, Antti (2019)
    Background Hip dysplasia and osteoarthritis continue to be prevalent problems in veterinary and human medicine. Canine hip dysplasia is particularly problematic as it massively affects several large-sized breeds and can cause a severe impairment of the quality of life. In Finland, the complex condition is categorized to five classes from normal to severe dysplasia, but the categorization includes several sub-traits: congruity of the joint, Norberg angle, subluxation degree of the joint, shape and depth of the acetabulum, and osteoarthritis. Hip dysplasia and osteoarthritis have been proposed to have separate genetic etiologies. Results Using Federation Cynologique Internationale -standardized ventrodorsal radiographs, German shepherds were rigorously phenotyped for osteoarthritis, and for joint incongruity by Norberg angle and femoral head center position in relation to dorsal acetabular edge. The affected dogs were categorized into mild, moderate and severe dysplastic phenotypes using official hip scores. Three different genome-wide significant loci were uncovered. The strongest candidate genes for hip joint incongruity were noggin (NOG), a bone and joint developmental gene on chromosome 9, and nanos C2HC-type zinc finger 1 (NANOS1), a regulator of matrix metalloproteinase 14 (MMP14) on chromosome 28. Osteoarthritis mapped to a long intergenic region on chromosome 1, between genes encoding for NADPH oxidase 3 (NOX3), an intriguing candidate for articular cartilage degradation, and AT-rich interactive domain 1B (ARID1B) that has been previously linked to joint laxity. Conclusions Our findings highlight the complexity of canine hip dysplasia phenotypes. In particular, the results of this study point to the potential involvement of specific and partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderate-to-severe dysplasia and osteoarthritis of canine hip joints. Further studies should unravel the unique and common mechanisms for the various sub-traits.
  • Mikkola, Lea; Holopainen, Saila; Lappalainen, Anu; Pessa-Morikawa, Tiina; Pulikotial Augustine, Thomas; Arumilli, Meharji; Hytönen, Marjo Kristiina; Hakosalo, Osmo Topi Valtteri; Lohi, Hannes; Iivanainen, Antti (2019)
    Canine hip dysplasia is a common, non-congenital, complex and hereditary disorder. It can inflict severe pain via secondary osteoarthritis and lead to euthanasia. An analogous disorder exists in humans. The genetic background of hip dysplasia in both species has remained ambiguous despite rigorous studies. We aimed to investigate the genetic causes of this disorder in one of the high-risk breeds, the German Shepherd. We performed genetic analyses with carefully phenotyped case-control cohorts comprising 525 German Shepherds. In our genome-wide association studies we identified four suggestive loci on chromosomes 1 and 9. Targeted resequencing of the two loci on chromosome 9 from 24 affected and 24 control German Shepherds revealed deletions of variable sizes in a putative enhancer element of the NOG gene. NOG encodes for noggin, a well-described bone morphogenetic protein inhibitor affecting multiple developmental processes, including joint development. The deletion was associated with the healthy controls and mildly dysplastic dogs suggesting a protective role against canine hip dysplasia. Two enhancer variants displayed a decreased activity in a dual luciferase reporter assay. Our study identifies novel loci and candidate genes for canine hip dysplasia, with potential regulatory variants in the NOG gene. Further research is warranted to elucidate how the identified variants affect the expression of noggin in canine hips, and what the potential effects of the other identified loci are.
  • Mölsä, Sari H; Hyytiäinen, Heli K; Morelius, Kaj M; Palmu, Maria K; Pesonen, Tommi S; Lappalainen, Anu K (BioMed Central, 2020)
    Abstract Background English bulldogs are known to be prone to skeletal problems, but knowledge is lacking of the effect of these problems on locomotion and function. This study was undertaken to report the conformational, orthopaedic and radiographic findings in a cohort of English bulldogs in Finland and to evaluate how these findings affect weight bearing and locomotion of the dogs. Twenty-eight English bulldogs were prospectively recruited to this cross-sectional study. An orthopaedic examination, measurements of conformation, static and dynamic weight bearing, and radiographic examinations of elbow, hip, stifle joints and spine were done. Results The English bulldogs carried a mean of 67.3% and 62.1% of their body weight in front limbs while standing and trotting, respectively. Front and hind limb lameness was seen in 20.8% (5/24) and 12.5% (3/24) of dogs, respectively. At orthopaedic examination, abnormal palpation findings (i.e. pain response, crepitation, swelling or subjectively decreased range of motion) were observed in a median of one joint (range 0–5) in each dog. Medial patellar luxation was diagnosed in 33.0% (8/24) of the evaluated dogs. At radiographic examination, elbow dysplasia was diagnosed in 48.2% (27/56) of elbow joints and severe hip dysplasia in 55.4% (31/56) of hip joints. The grade of elbow dysplasia was negatively associated with the ratio of static weight bearing between the front and hind limbs (slope estimate − 1.46, 95% CI − 2.75 to − 0.16, P = 0.03) and in dynamic weight bearing the ratio of total pressure index between the front and hind limbs (slope estimate − 0.088, 95% CI − 0.164 to 0.025, P = 0.03). The severity of hip dysplasia or hip osteoarthritis was not associated with the amount of static or dynamic weight bearing, but all except one dog were diagnosed with Fédération Cynologique Internationale grade C, D or E hips (dysplastic). In the spine, 78.6% (22/28) of the dogs had at least one malformed vertebra. Conclusions Orthopaedic diseases and abnormal radiographic findings were common in the English bulldogs studied. The static weight bearing of the dogs was heavily distributed to the front limbs. With increasing severity of elbow dysplasia, the static and dynamic weight bearing shifted from dysplastic elbows to hind limbs.
  • Mölsä, Sari Helena; Hyytiäinen, Heli Katariina; Morelius, Kaj Mikael; Palmu, Maria Katariina; Pesonen, Tommi Sakari; Lappalainen, Anu Katriina (2020)
    Background English bulldogs are known to be prone to skeletal problems, but knowledge is lacking of the effect of these problems on locomotion and function. This study was undertaken to report the conformational, orthopaedic and radiographic findings in a cohort of English bulldogs in Finland and to evaluate how these findings affect weight bearing and locomotion of the dogs. Twenty-eight English bulldogs were prospectively recruited to this cross-sectional study. An orthopaedic examination, measurements of conformation, static and dynamic weight bearing, and radiographic examinations of elbow, hip, stifle joints and spine were done. Results The English bulldogs carried a mean of 67.3% and 62.1% of their body weight in front limbs while standing and trotting, respectively. Front and hind limb lameness was seen in 20.8% (5/24) and 12.5% (3/24) of dogs, respectively. At orthopaedic examination, abnormal palpation findings (i.e. pain response, crepitation, swelling or subjectively decreased range of motion) were observed in a median of one joint (range 0-5) in each dog. Medial patellar luxation was diagnosed in 33.0% (8/24) of the evaluated dogs. At radiographic examination, elbow dysplasia was diagnosed in 48.2% (27/56) of elbow joints and severe hip dysplasia in 55.4% (31/56) of hip joints. The grade of elbow dysplasia was negatively associated with the ratio of static weight bearing between the front and hind limbs (slope estimate - 1.46, 95% CI - 2.75 to - 0.16, P = 0.03) and in dynamic weight bearing the ratio of total pressure index between the front and hind limbs (slope estimate - 0.088, 95% CI - 0.164 to 0.025, P = 0.03). The severity of hip dysplasia or hip osteoarthritis was not associated with the amount of static or dynamic weight bearing, but all except one dog were diagnosed with Federation Cynologique Internationale grade C, D or E hips (dysplastic). In the spine, 78.6% (22/28) of the dogs had at least one malformed vertebra. Conclusions Orthopaedic diseases and abnormal radiographic findings were common in the English bulldogs studied. The static weight bearing of the dogs was heavily distributed to the front limbs. With increasing severity of elbow dysplasia, the static and dynamic weight bearing shifted from dysplastic elbows to hind limbs.