Equine vitiligo-like depigmentation in grey horses is related to genes involved in immune response and tumor metastasis.
Abstract: In horses, the autoimmune disease vitiligo is characterized by the loss of melanocytes and results in patchy depigmentation of the skin around the eyes, muzzle and the perianal region. Vitiligo-like depigmentation occurs predominantly in horses displaying the grey coat colour and is observed at a prevalence level of 26.0-67.0% in grey horses compared with only 0.8-3.5% in non-grey horses. While the polygenetic background of this complex disease is well documented in humans, the underlying candidate genes for this skin disorder in horses remain unknown. In this study we aim to perform a genome-wide association study (GWAS) for identifying putative candidate loci for vitiligo-like depigmentation in horses. Methods: In the current study, we performed a GWAS analysis using high-density 670 k single nucleotide polymorphism (SNP) data from 152 Lipizzan and 104 Noriker horses, which were phenotyped for vitiligo-like depigmentation by visual inspection. After quality control 376,219 SNPs remained for analyses, the genome-wide Bonferroni corrected significance level was p < 1.33e-7. Results: We identified seven candidate genes on four chromosomes (ECA1, ECA13, ECA17, ECA20) putatively involved in vitiligo pathogenesis in grey horses. The highlighted genes PHF11, SETDB2, CARHSP1 and LITAFD, are associated with the innate immune system, while the genes RCBTB1, LITAFD, NUBPL, PTP4A1, play a role in tumor suppression and metastasis. The antagonistic pathogenesis of vitiligo in relation to cancer specific enhanced cell motility and/or metastasis on typical melanoma predilection sites underlines a plausible involvement of RCBTB1, LITAFD, NUBPL, and PTP4A1. Conclusions: The proposed candidate genes for equine vitiligo-like depigmentation, indicate an antagonistic relation between vitiligo and tumor metastasis in a horse population with higher incidence of melanoma. Further replication and expression studies should lead to a better understanding of this skin disorder in horses.
© 2021. The Author(s).
Publication Date: 2021-10-25 PubMed ID: 34696794PubMed Central: PMC8543801DOI: 10.1186/s12917-021-03046-xGoogle Scholar: Lookup
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Summary
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The research article presents the results of a study that aimed to identify the genes involved in the onset of vitiligo-like skin depigmentation in grey horses, which is a higher prevalence compared to non-grey horses. The findings propose an antagonistic link between vitiligo and tumor metastasis in a horse population with a higher incidence of melanoma.
Study Objective and Methodology
- The researchers set out to perform a genome-wide association study (GWAS) to identify potential candidate genes responsible for vitiligo-like depigmentation in horses. This came out of the observation that this condition is predominant in grey horses, with a health prevalence of up to 67%, compared to a maximum of 3.5% in non-grey horses.
- To carry out this study, the team used high-density 670k single nucleotide polymorphism (SNP) data from a sample of 256 horses, compromised of 152 Lipizzan and 104 Noriker horses. These animals were phenotypically characterized for vitiligo-like depigmentation through visual inspection. Following quality control measures, the team analyzed 376,219 SNPs utilizing a genome-wide Bonferroni corrected significance level of p < 1.33e-7.
Findings
- The study produced seven candidate genes on four chromosomes (ECA1, ECA13, ECA17, ECA20) that are potentially implicated in the occurrence of vitiligo in grey horses.
- These identified genes, comprising of PHF11, SETDB2, CARHSP1, LITAFD, RCBTB1, NUBPL, PTP4A1, displayed connections with either the immune system or played roles in tumor suppression and metastasis.
- Among these, PHF11, SETDB2, CARHSP1, and LITAFD are associated with the body’s innate immune response. Conversely, RCBTB1, LITAFD, NUBPL, PTP4A1 are known for their roles in controlling tumor growth and the spread (metastasis) of tumors.
Conclusions and Implications
- The results suggest a plausible antagonistic relationship between vitiligo and tumor metastasis, particularly within a horse population that has a higher rate of melanoma.
- The study recommends further research, especially replication and expression studies, to gain a clearer understanding of vitiligo-like depigmentation in horses.
- If validated by future research, these initial findings could prove helpful for therapeutic interventions, not only in grey horses suffering from this skin disorder but potentially in human vitiligo and tumor metastasis understandings.
Cite This Article
APA
Druml T, Brem G, Velie B, Lindgren G, Horna M, Ricard A, Grilz-Seger G.
(2021).
Equine vitiligo-like depigmentation in grey horses is related to genes involved in immune response and tumor metastasis.
BMC Vet Res, 17(1), 336.
https://doi.org/10.1186/s12917-021-03046-x Publication
Researcher Affiliations
- Institute of Animal Breeding and Genetics, University of Veterinary sciences Vienna, Veterinärplatz 1, A-1210, Vienna, Austria. thomas.druml@gmx.at.
- Institute of Animal Breeding and Genetics, University of Veterinary sciences Vienna, Veterinärplatz 1, A-1210, Vienna, Austria.
- Equine Genetics & Genomics Group, School of Life & Environmental Sciences, University of Sydney, Sydney, Australia.
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences Uppsala, Uppsala, Sweden.
- Livestock Genetics, Department of Biosystems, KU Leuven, Leuven, Belgium.
- Department of Animal Husbandry, Slovak University of Agriculture in Nitra, Nitra, Slovakia.
- GABI, INRAE, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
- Pôle Développement Innovation Recherche, IFCE, 61310, Gouffern en Auge, France.
- Institute of Animal Breeding and Genetics, University of Veterinary sciences Vienna, Veterinärplatz 1, A-1210, Vienna, Austria.
MeSH Terms
- Animals
- Gene Expression Regulation / immunology
- Genetic Predisposition to Disease
- Genotype
- Horse Diseases / genetics
- Horse Diseases / pathology
- Horses
- Immunity, Innate / genetics
- Melanoma / genetics
- Melanoma / pathology
- Melanoma / veterinary
- Neoplasm Metastasis / genetics
- Pigmentation Disorders / genetics
- Pigmentation Disorders / veterinary
- Polymorphism, Single Nucleotide
- Prevalence
Conflict of Interest Statement
The authors declare that there are no competing interests.
References
This article includes 57 references
- Kingsley IE, Harris JE. Animal models of vitiligo: matching the model to the question.. Dermatol Sin 2014;32:240–247.
- Shen C, Gao J, Sheng Y, Dou J, Zhou F, Zheng X, Ko R, Tang X, Zhu C, Yin X, Sun L, Cui Y, Zhang X. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.. Front Genet 2016;7:3.
- Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristics of melanocytes obtained from adult normal and vitiligo subjects.. J Invest Dermatol 1987 Apr;88(4):434-8.
- Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo.. Br J Dermatol 2001 Jan;144(1):55-65.
- Kroll TM, Bommiasamy H, Boissy RE, Hernandez C, Nickoloff BJ, Mestril R, Caroline Le Poole I. 4-Tertiary butyl phenol exposure sensitizes human melanocytes to dendritic cell-mediated killing: relevance to vitiligo.. J Invest Dermatol 2005 Apr;124(4):798-806.
- Yu R, Huang Y, Zhang X, Zhou Y. Potential role of neurogenic inflammatory factors in the pathogenesis of vitiligo.. J Cutan Med Surg 2012 Jul-Aug;16(4):230-44.
- Ogg GS, Rod Dunbar P, Romero P, Chen JL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo.. J Exp Med 1998 Sep 21;188(6):1203-8.
- Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Schittek B, Knauss-Scherwitz E, Stevanovic S, Rammensee HG, Garbe C. HLA-A2 restricted, melanocyte-specific CD8(+) T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanA/MART1.. J Invest Dermatol 2001 Jun;116(6):891-7.
- Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE. New discoveries in the pathogenesis and classification of vitiligo.. J Am Acad Dermatol 2017 Jul;77(1):1-13.
- Jin Y, Andersen G, Yorgov D, Ferrara TM, Ben S, Brownson KM, Holland PJ, Birlea SA, Siebert J, Hartmann A, Lienert A, van Geel N, Lambert J, Luiten RM, Wolkerstorfer A, Wietze van der Veen JP, Bennett DC, Taïeb A, Ezzedine K, Kemp EH, Gawkrodger DJ, Weetman AP, Kõks S, Prans E, Kingo K, Karelson M, Wallace MR, McCormack WT, Overbeck A, Moretti S, Colucci R, Picardo M, Silverberg NB, Olsson M, Valle Y, Korobko I, Böhm M, Lim HW, Hamzavi I, Zhou L, Mi QS, Fain PR, Santorico SA, Spritz RA. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.. Nat Genet 2016 Nov;48(11):1418-1424.
- Gupta I, Narang A, Singh P, Manchanda V, Khanna S, Mukerji M, Natarajan VT, Dash D. VitiVar: A locus specific database of vitiligo associated genes and variations.. Gene X 2019 Sep;3:100018.
- Kundu RV, Mhlaba JM, Rangel SM, Le Poole IC. The convergence theory for vitiligo: A reappraisal.. Exp Dermatol 2019 Jun;28(6):647-655.
- Lei Z, Yu S, Ding Y, Liang J, Halifu Y, Xiang F, Zhang D, Wang H, Hu W, Li T, Wang Y, Zou X, Zhang K, Kang X. Identification of key genes and pathways involved in vitiligo development based on integrated analysis.. Medicine (Baltimore) 2020 Jul 31;99(31):e21297.
- Tham HL, Linder KE, Olivry T. Autoimmune diseases affecting skin melanocytes in dogs, cats and horses: vitiligo and the uveodermatological syndrome: a comprehensive review.. BMC Vet Res 2019 Jul 19;15(1):251.
- Naughton GK, Mahaffey M, Bystryn JC. Antibodies to surface antigens of pigmented cells in animals with vitiligo.. Proc Soc Exp Biol Med 1986 Mar;181(3):423-6.
- Meijer WC. Dermatological diagnosis in horse and cattle judging.. Vet Rec 1965 Sep 4;77(36):1046-7.
- Meijer WCP. Vitiligo in the horse: the so-called ‘neigeuses’.. Neth J Vet Sci 1961;86:1021–1026.
- Meijer WCP. Vitiligo in horses and cattle.. Neth J Vet Sci 1962;87:411–417.
- McLean LM, Jones WE. Depigmentation – copper supplement therapy a case report.. J Equine Vet Sci 1983;3:208–210.
- Montes LF, Wilborn WH, Hyde BM, Vaughan JT, Bennett JS. Vitiligo in a quarter horse filly: Clinicopathologic, ultrastructural and nutritional study.. J Equine Vet Sci 2008;28:171–175.
- Mozos E, Novales M, sierra MA. Focal hypopigmentation in horses resembling Arabian fading syndrome.. Equine Vet Educ 1991;3:122–125.
- Scott DW, Miller WH. Pigmentary abnormalities.. In: Scott DW, Miller WH, editors. Equine Dermatology. 2. Maryland Heights: Elsevier/ Saunders; 2011. pp. 391–392.
- Rosengren Pielberg G, Golovko A, Sundström E, Curik I, Lennartsson J, Seltenhammer MH, Druml T, Binns M, Fitzsimmons C, Lindgren G, Sandberg K, Baumung R, Vetterlein M, Strömberg S, Grabherr M, Wade C, Lindblad-Toh K, Pontén F, Heldin CH, Sölkner J, Andersson L. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.. Nat Genet 2008 Aug;40(8):1004-9.
- Curik I, Druml T, Seltenhammer M, Sundström E, Pielberg GR, Andersson L, Sölkner J. Complex inheritance of melanoma and pigmentation of coat and skin in Grey horses.. PLoS Genet 2013;9(2):e1003248.
- Hofmanová B, Vostrý L, Majzlík I, Vostrá-Vydrová H. Characterization of greying, melanoma, and vitiligo quantitative inheritance in old Kladruber horses.. Czech J Anim Sci 2015;60:443–451.
- Sánchez-Guerrero MJ, Solé M, Azor PJ, Sölkner J, Valera M. Genetic and environmental risk factors for vitiligo and melanoma in Pura Raza Español horses.. Equine Vet J 2019 Sep;51(5):606-611.
- Seltenhammer MH, Simhofer H, Scherzer S, Zechner R, Curik I, Sölkner J, Brandt SM, Jansen B, Pehamberger H, Eisenmenger E. Equine melanoma in a population of 296 grey Lipizzaner horses.. Equine Vet J 2003 Mar;35(2):153-7.
- Teulings HE, Overkamp M, Ceylan E, Nieuweboer-Krobotova L, Bos JD, Nijsten T, Wolkerstorfer AW, Luiten RM, van der Veen JP. Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners.. Br J Dermatol 2013 Jan;168(1):162-71.
- Paradisi A, Tabolli S, Didona B, Sobrino L, Russo N, Abeni D. Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo.. J Am Acad Dermatol 2014 Dec;71(6):1110-6.
- Spritz RA. The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma.. Genome Med 2010 Oct 19;2(10):78.
- Spritz RA, Andersen GH. Genetics of Vitiligo.. Dermatol Clin 2017 Apr;35(2):245-255.
- Misfeldt ML, Grimm DR. Sinclair miniature swine: an animal model of human melanoma.. Vet Immunol Immunopathol 1994 Oct;43(1-3):167-75.
- Lentz KJ, Burns RP, Loeffler K, Feeney-Burns L, Berkelhammer J, Hook RR Jr. Uveitis caused by cytotoxic immune response to cutaneous malignant melanoma in swine: destruction of uveal melanocytes during tumor regression.. Invest Ophthalmol Vis Sci 1983 Aug;24(8):1063-9.
- Hoek KS. DNA microarray analyses of melanoma gene expression: a decade in the mines.. Pigment Cell Res 2007 Dec;20(6):466-84.
- Wang Y, Wu N, Sun D, Sun H, Tong D, Liu D, Pang B, Li S, Wei J, Dai J, Liu Y, Bai J, Geng J, Fu S, Jin Y. NUBPL, a novel metastasis-related gene, promotes colorectal carcinoma cell motility by inducing epithelial-mesenchymal transition.. Cancer Sci 2017 Jun;108(6):1169-1176.
- Savoia P, Fava P, Casoni F, Cremona O. Targeting the ERK Signaling Pathway in Melanoma.. Int J Mol Sci 2019 Mar 25;20(6).
- Jang N, Stewart G, Jones G. Polymorphisms within the PHF11 gene at chromosome 13q14 are associated with childhood atopic dermatitis.. Genes Immun 2005 May;6(3):262-4.
- Holt RJ, Vandiedonck C, Willis-Owen SA, Knight JC, Cookson WO, Moffatt MF, Zhang Y. A functional AT/G polymorphism in the 5'-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14.. Genes Immun 2015 Oct;16(7):488-94.
- Torrano J, Al Emran A, Hammerlindl H, Schaider H. Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming.. Clin Epigenetics 2019 Mar 8;11(1):43.
- Kimball AS, Davis FM, denDekker A, Joshi AD, Schaller MA, Bermick J, Xing X, Burant CF, Obi AT, Nysz D, Robinson S, Allen R, Lukacs NW, Henke PK, Gudjonsson JE, Moore BB, Kunkel SL, Gallagher KA. The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.. Immunity 2019 Aug 20;51(2):258-271.e5.
- Mabuchi H, Fujii H, Calin G, Alder H, Negrini M, Rassenti L, Kipps TJ, Bullrich F, Croce CM. Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia.. Cancer Res 2001 Apr 1;61(7):2870-7.
- Zhou X, Münger K. Clld7, a candidate tumor suppressor on chromosome 13q14, regulates pathways of DNA damage/repair and apoptosis.. Cancer Res 2010 Nov 15;70(22):9434-43.
- Bessette DC, Qiu D, Pallen CJ. PRL PTPs: mediators and markers of cancer progression.. Cancer Metastasis Rev 2008 Jun;27(2):231-52.
- Sacchetti C, Bai Y, Stanford SM, Di Benedetto P, Cipriani P, Santelli E, Piera-Velazquez S, Chernitskiy V, Kiosses WB, Ceponis A, Kaestner KH, Boin F, Jimenez SA, Giacomelli R, Zhang ZY, Bottini N. PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.. Nat Commun 2017 Oct 20;8(1):1060.
- Pfeiffer JR, McAvoy BL, Fecteau RE, Deleault KM, Brooks SA. CARHSP1 is required for effective tumor necrosis factor alpha mRNA stabilization and localizes to processing bodies and exosomes.. Mol Cell Biol 2011 Jan;31(2):277-86.
- Takashiba S, Van Dyke TE, Shapira L, Amar S. Lipopolysaccharide-inducible and salicylate-sensitive nuclear factor(s) on human tumor necrosis factor alpha promoter.. Infect Immun 1995 Apr;63(4):1529-34.
- Bertolo C, Roa S, Sagardoy A, Mena-Varas M, Robles EF, Martinez-Ferrandis JI, Sagaert X, Tousseyn T, Orta A, Lossos IS, Amar S, Natkunam Y, Briones J, Melnick A, Malumbres R, Martinez-Climent JA. LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas.. Br J Haematol 2013 Sep;162(5):621-30.
- Grilz-Seger G, Druml T, Neuditschko M, Dobretsberger M, Horna M, Brem G. High-resolution population structure and runs of homozygosity reveal the genetic architecture of complex traits in the Lipizzan horse.. BMC Genomics 2019 Mar 5;20(1):174.
- Grilz-Seger G, Dobretsberger M, Brem G, Druml T. Untersuchungen zum Allelstatus einzelner Farbloci und Abzeichen beim Lipizzaner.. Züchtungskunde 2020;92:76–86.
- Grilz-Seger G, Neuditschko M, Ricard A, Velie B, Lindgren G, Mesarič M, Cotman M, Horna M, Dobretsberger M, Brem G, Druml T. Genome-Wide Homozygosity Patterns and Evidence for Selection in a Set of European and Near Eastern Horse Breeds.. Genes (Basel) 2019 Jun 28;10(7).
- Schaefer RJ, Schubert M, Bailey E, Bannasch DL, Barrey E, Bar-Gal GK, Brem G, Brooks SA, Distl O, Fries R, Finno CJ, Gerber V, Haase B, Jagannathan V, Kalbfleisch T, Leeb T, Lindgren G, Lopes MS, Mach N, da Câmara Machado A, MacLeod JN, McCoy A, Metzger J, Penedo C, Polani S, Rieder S, Tammen I, Tetens J, Thaller G, Verini-Supplizi A, Wade CM, Wallner B, Orlando L, Mickelson JR, McCue ME. Developing a 670k genotyping array to tag ~2M SNPs across 24 horse breeds.. BMC Genomics 2017 Jul 27;18(1):565.
- Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses.. Am J Hum Genet 2007 Sep;81(3):559-75.
- Corbin LJ, Pope J, Sanson J, Antczak DF, Miller D, Sadeghi R, Brooks SA. An Independent Locus Upstream of ASIP Controls Variation in the Shade of the Bay Coat Colour in Horses.. Genes (Basel) 2020 May 30;11(6).
- Rieder S, Taourit S, Mariat D, Langlois B, Guérin G. Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus).. Mamm Genome 2001 Jun;12(6):450-5.
- Kavar T, Čeh E, Dovč P. A simplified PCR-based method for detection of gray coat color allele in horse.. Mol Cell Probes 2012 Dec;26(6):256-8.
- SAS Institute. SAS university edition. 2021. Cary (NC): SAS institute, Inc.
- Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis.. Am J Hum Genet 2011 Jan 7;88(1):76-82.
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