Polymorphisms of the COL9A2, AOAH and FRZB Genes in the Horse Genome and their Association with the Occurrence of Osteochondrosis

Wypchło, Maria; Korwin-Kossakowska, Agnieszka; Bereznowski, Andrzej; Hecold, Mateusz; Lewczuk, Dorota

doi:10.1515/aoas-2016-0072

Abstract

The aim of the study was to evaluate the chosen polymorphisms of the COL9A2, AOAH and FRZB genes and find their potential effect on the occurrence of osteochondrosis in Polish sport horses population. During two successive years, all 198 performance tested horses were checked for osteochondrosis. The health status of the horses was assessed based on 10 x-ray images of three joints: fetlock, hock and stifle, and scored on a 0-3 scale. The methodology of analysis of selected candidate genes using the PCR-RFLP technique was developed. The analysis of variance was performed to evaluate significance of the effect of the COL9A2, AOAH and FRZB genotype on the occurrence of osteochondrosis in individual joints. Fixed effects of breed, gender and training centre were taken into account in the analysis. The results showed a significant influence (P≤0.05) of the COL9A2 genotypes on the occurrence of osteochondrosis in fetlock and hock joints. Polymorphism of this gene, even not proved a causal mutation, appears to have effect on symptoms of the disease. In genes AOAH and FRZB there was no significant effect for investigated SNPs. Further analysis of the discussed genes/polymorphisms seems to be important.

References

Annunen S., Paassilta P., Lohiniva J., Perälä M., Pihlajamaa T., Karppinen J., Tervonen O., Kr öger H., L ähde S., Vanharanta H., Ryhänen L., Goring H.H.H., Ott J., Prockop D.J., Ala- Kokko L. (1999). An allele of COL9A2 associated with intervertebral disc disease. Science, 285: 409-412.
Search in Google Scholar Back to article
Baker- Le Pain J.C., Lynch J.A., Parimi N., Mc Culloch Ch.E., Nevitt M.C., Corr M., Lane N.E. (2012). Variant alleles of the WNTantagonist FRZBare determinants of hip shape and modify the relationship between hip shape and osteoarthritis. Arthritis Rheum., 64: 1457-1465.
Search in Google Scholar Back to article
Bates J.T., Jacobs Jr. J.C., Shea K.G., Oxford J.T. (2014). Emerging genetic basis of osteochondritis dissecans. Clin Sports Med., 33: 199-210.
Search in Google Scholar Back to article
Böneker C., Kuiper H., Dr ögemüller C., Chowdhary B.P., Distel O. (2006). Molecular characterization of the equine collagen, type IX, alpha 2 (COL9A2) gene on horse chromosome 2p16→p15. Cytogenet. Genome Res., 115: 107-114.
Search in Google Scholar Back to article
Chowdhary B.P., Raudsepp T., Kata S.R., Goh G., Millon L.V., Allan V., Piumi F., Gue´rin G., Swinburne J., Binns M., Lear T.L., Mickelson J., Murray J., Antczak D.F., Womack J.E., Skow L.C. (2003). The first-generation whole-genome radiation hybrid map in the horse identifies conserved segments in human and mouse genomes. Genome Res., 13: 742-751.
Search in Google Scholar Back to article
Corbin L.J., Blott S.C., Swinburne J.E., Sibbons C., Fox- Clipsham L.Y., Helwegen M., Parkin T.D.H., Newton J.R., Bramlage L.R., Mc Ilwraith C.W., Bishop S.C., Woollians J.A., Vaudin M. (2012). Agenome-wide association study of osteochondritis dissecans in the Thoroughbred. Mamm. Genome, 23: 294-303.
Search in Google Scholar Back to article
Distl O. (2013). The genetics of equine osteochondrosis. Vet. J., 197: 13-18.
Search in Google Scholar Back to article
Dong Y., Drissi H., Chen M., Chen D., Zuscik M.J., Schwarz E.M., O ’ Keefe R.J. (2005). Wnt-mediated regulation of chondrocyte maturation: modulation by TGF-β. J. Cell. Biochem., 95: 1057-1068.
Search in Google Scholar Back to article
Enochson L., Stenberg J., Brittberg M., Lindahl A. (2014). GDF5 reduces MMP13 expression in human chondrocytes via DKK1 mediated canonical Wnt signaling inhibition. Osteoarthr. Cartilage, 22: 566-577.
Search in Google Scholar Back to article
Enomoto- Iwamoto M., Kitagaki J., Koyama E., Tamamura Y., Wu C., Kanatani N., Koike T., Okada H., Komori T., Yoneda T., Church V., Francis- West P.H., Kurisu K., Nohono T., Pacifici M., Iwamoto M. (2002). The Wnt antagonist Frzb- 1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev Biol., 251: 142-156.
Search in Google Scholar Back to article
Falconer D.S. (1965). Inheritance of liability to certain diseases estimated from incidence among relatives. Ann. Hum. Genet., 29: 51.
Search in Google Scholar Back to article
Fiedler J., Stöve J., Heber F., Brenner R.E. (2002). Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2). Am. J. Med. Genet., 112: 144-153.
Search in Google Scholar Back to article
Goldstein O., Guyon R., Kukekova A., Pearce - Kelling S., Johnson J., Aguirre G.D., Acland G.M. (2010). COL9A2 and COL9A3 mutations in canine autosomal recessive oculo-skeletal dysplasia. Mamm. Genome, 21: 398-408.
Search in Google Scholar Back to article
Holden P., Canty G.C., Mortier G.R., Zabel B., Spranger J., Carr A., Grant M.E., Loughlin J.A., Briggs M.D. (1999). Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia. Am. J. Hum. Genet., 65: 31-38.
Search in Google Scholar Back to article
Ikeda T., Mabuchi A., Fukuda A., Kawakami A., Yamada R., Yamamoto S., Miyoshi K., Haga N., Hiraoka H., Takatori Y., Kawaguchi H., Nakamura K., Ikegawa S. (2002). Association analysis of single nucleotide polymorphisms in cartilage-specific collagen genes with knee and hip osteoarthritis in the Japanese population. JBMR, 17: 1290-1296.
Search in Google Scholar Back to article
Jeffcott L.B., Henson F.M.D. (1998). Studies on growth cartilage in the horse and their application to aetiopathogenesis of dyschondroplasia (osteochondrosis). Vet. J., 156: 177-192.
Search in Google Scholar Back to article
Komm K. (2010). Fine mapping of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horse. Thesis, Hannover.
Search in Google Scholar Back to article
Lampe V. (2009). Fine mapping of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horses. Dissertation, Hannover.
Search in Google Scholar Back to article
Lane N.E., Lian K., Nevitt M.C., Zmuda J.M., Lui L., Wang J., Fontecha M., Umblas N., Rosenbach M.,de Leon P., Corr M. (2006). Frizzled-related protein variants are risk factors for hip osteoarthritis. Arthritis Rheum., 54: 1246-1254.
Search in Google Scholar Back to article
Lane N.E., Nevitt M.C., Lui Li-Y.,de Leon P., Corr M. (2007). Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women. Arthritis Rheum., 56: 3319-3325.
Search in Google Scholar Back to article
Leijten J.C.H., Emos J., Sticht C.,van Gool S., Decker E., Uitterlinden A., Rappold G., Hofman A., Rivadeneira F., Scherjon S., Wit J.M.,van Meurs J.,va n Blitterswijk A., Karperien M. (2012). Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis. Arthritis Rheum., 64: 3302-3312.
Search in Google Scholar Back to article
Lewczuk D., Korwin - Kossakowska A. (2012). Genetic background of osteochondrosis in the horse. Anim. Sci. Pap. Rep., 30: 205-218.
Search in Google Scholar Back to article
Lewczuk D., Berezowski A., Hecold M., Kłos Z. (2011). Częstość występowania martwicy chrzęsto-kostnejuogieróww Zakładach Treningowych - doniesienie wstępne (in Polish). Rocz. Nauk. PTZ, 3: 31-38.
Search in Google Scholar Back to article
Lodewyckx L., Lories R.J.U. (2009). WNTsignaling in osteoarthritis and osteoporosis: what is the biological significance for the clinician? Curr. Rheumatol. Rep., 11: 23-30.
Search in Google Scholar Back to article
Loughlin J., Dowling B., Chapman K., Marcelline L., Mustafa Z., Southam L., Ferreira A., Ciesielski C., Carson D.A., Corr M. (2004). Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc. Nat. Acad. Sci. USA, 101: 9757-9762.
Search in Google Scholar Back to article
Lykkjen S., Dolvik N.I., Mc Cue M.E., Rendahl A.K., Mickelson J.R., Roed K.H. (2010). Genome-wide association analysis of osteochondrosis of the tibiotarsal joint in Norwegian Standardbred trotters. Anim. Genet., 41: 111-120.
Search in Google Scholar Back to article
Lykkjen S., Dolvik N.I., Mc Cue M.E., Rendahl A.K., Mickelson J.R., Røed K.H. (2013). Equine developmental orthopaedic diseases -agenome-wide association study of first phalanx plantar osteochondral fragments in Standardbred trotters. Anim. Genet., 44: 766-769.
Search in Google Scholar Back to article
Mc Coy A.M., Beeson S.K., Splan R.K., Lykkjen S., Ralston S.L., Mickelson J.R., Mc Cue M.E. (2016). Identification and validation of risk loci for osteochondrosis in standardbreds. BMC Genomics, 17: 41.
Search in Google Scholar Back to article
Mienaltowski M.J., Huang L., Stromberg A.J., Mac Leod J.N. (2008). Differential gene expression associated with postnatal equine articular cartilage maturation. BMC Musculoskel. Dis., 9: 149.
Search in Google Scholar Back to article
Minafra L., Bravatà V., Saporito M., Cammarata F.P., Forte G.I., Caldarella S., D ’ Arienzo M., Gilardi M.C., Messa C., Boniforti F. (2014). Genetic, clinical and radiographic signs in knee osteoarthritis susceptibility. Arthritis Res. Ther., 16: R91.
Search in Google Scholar Back to article
Penedo M.C.T., Millon L.V., Bernoco D., Bailey E., Binns M., Cholewinski G., Ellis N., Flynn J., Gralak B., Guthrie A., Hasegawa T., Lindgren G., Lyons L.A., R øed K.H., Swinburne J.E., Tozaki T. (2005). International equine gene mapping workshop report:acomprehensive linkage map constructed with data from new markers and by merging four mapping resources. Cytogenet. Genome Res., 111: 5-15.
Search in Google Scholar Back to article
Perrocheau M., Boutreux V., Chadi S., Mata X., Decaunes P., Raudsepp T., Durkin K., Incarnato D., Iannuzzl L., Lear T.L., Hirota K., Hasegawa T., Zhu B., de Jong P., Cribiu E.P., Chowdhary B.P., Gu érin G. (2006). Construction ofamediumdensity horse gene map. Anim. Genet., 37: 145-155.
Search in Google Scholar Back to article
Ramos Y.F.M.,den Hollander W., Bovée J.V.M.G., Bomer N.,vander Breggen R., Lakenberg N., Keurentjes J.Ch., Goeman J.J., Slagboom P.E., Nelissen R.G.H.H., Bos S.D., Meulenbelt I. (2014). Genes involved in the osteoarthritis process identified through genome wide expression analysis in articular cartilage; the RAAKstudy. PLo S One, 9(7): 103056.
Search in Google Scholar Back to article
Stock K.F., Distl O. (2005). Evaluation of expected response to selection for orthopedic health and performance traits in Hanoverian Warmblood horses. Am. J. Vet. Res., 66: 1371-1379.
Search in Google Scholar Back to article
Swinburne J.E., Boursnell M., Hill G., Pettitt L., Allen T., Chowdhary B., Hasegawa T., Kurosawa M., Leeb T., Mashima S., Mickelson J.R., Raudsepp T., Tozaki T., Binns M. (2006). Single linkage group per chromosome genetic linkage map for the horse, based on two three-generation, full-sibling, crossbred horse reference families. Genomics, 87: 1-39.
Search in Google Scholar Back to article
Takahashi M., Matsui Y., Goto T., Nishimura G., Ikegawa S., Ohashi H., Yasui N. (2006). Intrafamilial phenotypic diversity in multiple epiphyseal dysplasia associated witha COL9A2 mutation (EDM2). Clin. Rheumatol., 25: 591-595.
Search in Google Scholar Back to article
Takamatsu A., Ohkawara B., Ito M., Masuda A., Sakai T., Ishiguro N., Ohno K. (2014). Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling. PLo S One., 9(3): e92699.
Search in Google Scholar Back to article
Teyssedre S., Dupuis M.C., Guerin G., Schibler L., Denoix J.M., Elsen J.M., Ricard A. (2012). Genome-wide association studies for osteochondrosis in French Trotter horses. J. Anim. Sci., 90: 45-53.
Search in Google Scholar Back to article
Van Grevenhof E.M., Ott S., Hazeleger W.,van Weeren P.R., Bijma P., Kempb B. (2011). The effects of housing system and feeding level on the joint-specific prevalence of osteochondrosis in fattening pigs. Livest. Sci., 135: 53-61.
Search in Google Scholar Back to article
Van Weeren P.R. (2006). Etiology, diagnosis, and treatment of OC(D). Clin. Tech. Equine Pract., 5: 248-258.
Search in Google Scholar Back to article
Wagner M.L., Raudsepp T., Goh G., Agarwala R., Schäffer A.A., Dranchak P.K., Brinkmeyer - Langford C., Skow L.C., Chowdhary B.P., Mickelson J.R. (2006). A 1.3-Mb interval map of equine homologs of HSA2. Cytogenet. Genome Res., 112: 227-234.
Search in Google Scholar Back to article
Wallin L., Strandberg E., Phililsson J., Dalin G. (2000). Estimates of longevity and causes of culling and death in Swedish warmblood and coldblood horses. Livest. Prod. Sci., 63: 275-289.
Search in Google Scholar Back to article
Wittwer C., Hamann H., Rosenberger E., Distl O. (2007). Genetic parameters for the prevalence of osteochondrosis in the limb joints of South German Coldblood horses. J. Anim. Genet., 124: 203-327.
Search in Google Scholar Back to article
Wittwer C., Dierks C., Hamann H., Distl O. (2008). Associations between candidate gene markers ataquantitative trait locus on equine chromosome 4 responsible for osteochondrosis dissecans in fetlock joints of South German Coldblood horses. J. Heredity, 99: 125-129.
Search in Google Scholar Back to article
Wittwer C., Hamann H., Distl O. (2009). The candidate gene XIRP2 ataquantitative gene locus on equine chromosome 18 associated with osteochondrosis in fetlock and hock joints of South German coldblood horses. J. Heridity, 100: 481-486.
Search in Google Scholar Back to article
Yang Y., Sun W., Wang R., Lei C., Zho R., Tang Z., Li K. (2015). Wnt antagonist, secreted frizzled-related protein 1, is involved in prenatal skeletal muscle development and isatarget of mi RNA-1/206 in pigs. BMC Mol. Biol., 16: 4.
Search in Google Scholar Back to article
Ytrehus B., Carlson C.S., Ekman S. (2007). Etiology and pathogenesis of osteochondrosis. Vet. Pathol., 44: 429-448.
Search in Google Scholar Back to article
Ząbek T., Golonka P., Fornal A., Semik E. (2013). IHHgene polymorphism among three horse breeds and its application for association test in horses with osteochondrosis. Hereditas, 150:38-43.
Search in Google Scholar Back to article

Polymorphisms of the COL9A2, AOAH and FRZB Genes in the Horse Genome and their Association with the Occurrence of Osteochondrosis

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