Analyze Diet
Journal of veterinary internal medicine2022; 36(6); 2203-2212; doi: 10.1111/jvim.16582

Investigation of high gamma-glutamyltransferase syndrome in California Thoroughbred racehorses.

Abstract: Increases in serum gamma-glutamyltransferase (GGT) activity have been reported in Thoroughbred (TB) racehorses and associated with maladaptation to training but the underlying etiology remains unknown. Objective: Classify the etiology of high GGT syndrome in racing TBs by assessment of pancreatic enzymes, vitamin E concentrations, and both a candidate gene and whole genome association study. We hypothesized that a genetic variant resulting in antioxidant insufficiency or pancreatic dysfunction would be responsible for high GGT syndrome in TBs. Methods: A total of 138 California racing TBs. Amylase: n = 31 affected (serum GGT activity ≥60 IU/L), n = 52 control (serum GGT activity <40 IU/L). Lipase: n = 19 affected, n = 35 control. Serum α-tocopherol concentrations: n = 32 affected, n = 46 control. Genome-wide association study (GWAS): 36 affected, 58 control. Whole genome sequencing: n = 5 affected, n = 5 control. Methods: Biochemical and vitamin analytes were compared among cohorts. A GWAS was performed and a subset of TBs underwent whole genome sequencing to interrogate candidate genes and positional genetic regions. Results: Serum lipase and amylase activity and α-tocopherol concentrations did not differ between groups. No genetic variants were identified in 2 candidate genes (UGT1A1 and GGT1) that associated with the phenotype. Four single nucleotide polymorphisms (SNPs) approached a suggestive association with the phenotype (P = 2.15 × 10 ), defining a 100 kb region on chromosome 5 surrounding cluster of differentiation 1a (CD1A1), a transmembrane gene related to the major histocompatibility complex. Conclusions: An underlying genetic etiology may exist for high GGT syndrome in racing TBs, similar to genetic disorders in humans.
Publication Date: 2022-11-15 PubMed ID: 36377652PubMed Central: PMC9708438DOI: 10.1111/jvim.16582Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study aimed to identify the cause of high levels of gamma-glutamyltransferase (GGT), a condition often seen in Thoroughbred (TB) racehorses, through examining pancreatic enzymes and vitamin E concentrations, alongside genomic data. The findings suggest that there may be a potential genetic factor contributing to this condition in horses, similar to some human disorders.

Objective

  • The research aimed to classify the origin of high GGT syndrome, a condition often seen in Thoroughbred racehorses that has typically been associated with the animal’s poor coping with training. The cause of the condition had not previously been fully understood.

Methods

  • The researchers compared levels of the pancreatic enzymes amylase and lipase, as well as vitamin E concentrations, between affected horses (those with high levels of GGT) and a control group (those with normal GGT levels).
  • In addition, the team conducted a Genome-Wide Association Study (GWAS) and then carried out whole genome sequencing on a subset to investigate particular genes and genetic regions. This was done based on a hypothesis that a genetic variant causing lower antioxidant levels or pancreatic dysfunction might be responsible for high GGT syndrome.

Results

  • The results showed no differences in pancreatic enzyme activity or vitamin E levels between the two groups. There were also no genetic variants identified in two candidate genes of interest (UGT1A1 and GGT1), which were believed to possibly be linked to the condition.
  • However, the GWAS identified four single nucleotide polymorphisms (SNPs), genetic variations, that suggested a link to high GGT syndrome. These SNPs, small changes in DNA sequence, were located in a small region on chromosome 5 near the cluster of differentiation 1a (CD1A1) gene.

Conclusions

  • The research team concluded that there may be a genetic cause to high GGT syndrome in Thoroughbred racehorses. This possibility is suggested by the identification of SNPs near the CD1A1 gene.”

Cite This Article

APA
Peng S, Magdesian KG, Dowd J, Blea J, Carpenter R, Ho W, Finno CJ. (2022). Investigation of high gamma-glutamyltransferase syndrome in California Thoroughbred racehorses. J Vet Intern Med, 36(6), 2203-2212. https://doi.org/10.1111/jvim.16582

Publication

ISSN: 1939-1676
NlmUniqueID: 8708660
Country: United States
Language: English
Volume: 36
Issue: 6
Pages: 2203-2212

Researcher Affiliations

Peng, Sichong
  • Department of Population Health and Reproduction, University of California, Davis, California, USA.
Magdesian, K Gary
  • Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California, USA.
Dowd, Joseph
  • Equine Medical and Surgical Group, Arcadia, California, USA.
Blea, Jeffrey
  • Von Bleucher, Blea, Hunkin, DVM, Inc, Sierra Madre, California, USA.
Carpenter, Ryan
  • DVM, Sierra Madre, California, USA.
Ho, Wayne
  • Southern California Equine Foundation, Arcadia, California, USA.
Finno, Carrie J
  • Department of Population Health and Reproduction, University of California, Davis, California, USA.

MeSH Terms

  • Animals
  • alpha-Tocopherol
  • Amylases
  • gamma-Glutamyltransferase / genetics
  • Genome-Wide Association Study / veterinary
  • Horses / genetics
  • Lipase
  • Horse Diseases / genetics

Grant Funding

  • L40 TR001136 / NCATS NIH HHS
  • L40 TR001136 / National Center for Advancing Translational Sciences
  • NA / UC Davis Center for Equine Health
  • NA / Southern California Equine Foundation

Conflict of Interest Statement

Authors declare no conflict of interest.

References

This article includes 52 references
  1. Tyler-McGowan CM, Golland LC, Evans DL, Hodgson DR, Rose RJ. Haematological and biochemical responses to training and overtraining.. Equine Vet J Suppl 1999 Jul;(30):621-5.
  2. Mack SJ, Kirkby K, Malalana F, McGowan CM. Elevations in serum muscle enzyme activities in racehorses due to unaccustomed exercise and training.. Vet Rec 2014 Feb 8;174(6):145.
    pubmed: 24415762doi: 10.1136/vr.101669google scholar: lookup
  3. Rivero JL, van Breda E, Rogers CW, Lindner A, van Oldruitenborgh-Oosterbaan MM. Unexplained underperformance syndrome in sport horses: classification, potential causes and recognition.. Equine Vet J 2008 Sep;40(6):611-8.
    pubmed: 18356127doi: 10.2746/042516408x299118google scholar: lookup
  4. Snow DH, Gash SP, Rice D. Field observations on selenium status, whole blood glutathione peroxidase and plasma gamma‐glutamyl transferase activities in thoroughbred racehorses. In: Gillespie JR, Robinson NE, eds. Equine Exercise Physiology 2. Davis, CA: ICEEP Publications; 1987:494.
  5. Mann S, Ramsay JD, Wakshlag JJ, Stokol T, Reed S, Divers TJ. Investigating the pathogenesis of high-serum gamma-glutamyl transferase activity in Thoroughbred racehorses: A series of case-control studies.. Equine Vet J 2022 Jan;54(1):39-51.
    pubmed: 33555643doi: 10.1111/evj.13435google scholar: lookup
  6. Mann S, Ramsay JD, Wakshlag JJ, Stokol T, Reed S, Divers TJ. Investigating the pathogenesis of high-serum gamma-glutamyl transferase activity in Thoroughbred racehorses: A series of case-control studies.. Equine Vet J 2022 Jan;54(1):39-51.
    pubmed: 33555643doi: 10.1111/evj.13435google scholar: lookup
  7. Brobst DF. Pancreatic function. In: Kaneko JJ, Harvey JW, Bruss ML, eds. Clinical Biochemistry of Domestic Animals. 5th ed. San Diego, CA: Academic Press; 1997:353‐366.
  8. Braun JP, Benard P, Burgat V, Rico AG. Gamma Glutamyl Transferase in domestic animals.. Vet Res Commun 1983 Mar;6(2):77-90.
    pubmed: 6135267doi: 10.1007/bf02214900google scholar: lookup
  9. RUTTENBURG AM, GOLDBARG JA, PINEDA EP. SERUM GAMMA-GLUTAMYL TRANSPEPTIDASE ACTIVITY IN HEPATOBILIARY PANCREATIC DISEASE.. Gastroenterology 1963 Jul;45:43-8.
    pubmed: 14046310
  10. Lee DH, Blomhoff R, Jacobs DR Jr. Is serum gamma glutamyltransferase a marker of oxidative stress?. Free Radic Res 2004 Jun;38(6):535-9.
    pubmed: 15346644doi: 10.1080/10715760410001694026google scholar: lookup
  11. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome.. N Engl J Med 1995 Nov 2;333(18):1171-5.
    pubmed: 7565971doi: 10.1056/nejm199511023331802google scholar: lookup
  12. Aono S, Adachi Y, Uyama E, Yamada Y, Keino H, Nanno T, Koiwai O, Sato H. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome.. Lancet 1995 Apr 15;345(8955):958-9.
    pubmed: 7715297doi: 10.1016/s0140-6736(95)90702-5google scholar: lookup
  13. Koiwai O, Nishizawa M, Hasada K, Aono S, Adachi Y, Mamiya N, Sato H. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase.. Hum Mol Genet 1995 Jul;4(7):1183-6.
    pubmed: 8528206doi: 10.1093/hmg/4.7.1183google scholar: lookup
  14. Brand H, Diergaarde B, O'Connell MR, Whitcomb DC, Brand RE. Variation in the γ-glutamyltransferase 1 gene and risk of chronic pancreatitis.. Pancreas 2013 Jul;42(5):836-40.
  15. Bibas M, Zampa G, Procopio A, Guaitolini R. High serum gamma-glutamyltransferase concentrations in a family.. N Engl J Med 1994 Jun 23;330(25):1832-3.
    pubmed: 7910666doi: 10.1056/nejm199406233302518google scholar: lookup
  16. Finno CJ, Valberg SJ. A comparative review of vitamin E and associated equine disorders.. J Vet Intern Med 2012 Nov-Dec;26(6):1251-66.
  17. Menashe I, Rosenberg PS, Chen BE. PGA: power calculator for case-control genetic association analyses.. BMC Genet 2008 May 13;9:36.
    pmc: PMC2387159pubmed: 18477402doi: 10.1186/1471-2156-9-36google scholar: lookup
  18. 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.
    pmc: PMC5530493pubmed: 28750625doi: 10.1186/s12864-017-3943-8google scholar: lookup
  19. Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies.. Nat Genet 2012 Jun 17;44(7):821-4.
    pmc: PMC3386377pubmed: 22706312doi: 10.1038/ng.2310google scholar: lookup
  20. Wade CM, Giulotto E, Sigurdsson S, Zoli M, Gnerre S, Imsland F, Lear TL, Adelson DL, Bailey E, Bellone RR, Blöcker H, Distl O, Edgar RC, Garber M, Leeb T, Mauceli E, MacLeod JN, Penedo MC, Raison JM, Sharpe T, Vogel J, Andersson L, Antczak DF, Biagi T, Binns MM, Chowdhary BP, Coleman SJ, Della Valle G, Fryc S, Guérin G, Hasegawa T, Hill EW, Jurka J, Kiialainen A, Lindgren G, Liu J, Magnani E, Mickelson JR, Murray J, Nergadze SG, Onofrio R, Pedroni S, Piras MF, Raudsepp T, Rocchi M, Røed KH, Ryder OA, Searle S, Skow L, Swinburne JE, Syvänen AC, Tozaki T, Valberg SJ, Vaudin M, White JR, Zody MC, Lander ES, Lindblad-Toh K. Genome sequence, comparative analysis, and population genetics of the domestic horse.. Science 2009 Nov 6;326(5954):865-7.
    pmc: PMC3785132pubmed: 19892987doi: 10.1126/science.1178158google scholar: lookup
  21. Beeson SK, Schaefer RJ, Mason VC, McCue ME. Robust remapping of equine SNP array coordinates to Eq쪳.. Anim Genet 2019 Feb;50(1):114-115.
    pmc: PMC6349531pubmed: 30421446doi: 10.1111/age.12745google scholar: lookup
  22. Karolchik D, Hinrichs AS, Furey TS, Roskin KM, Sugnet CW, Haussler D, Kent WJ. The UCSC Table Browser data retrieval tool.. Nucleic Acids Res 2004 Jan 1;32(Database issue):D493-6.
    pmc: PMC308837pubmed: 14681465doi: 10.1093/nar/gkh103google scholar: lookup
  23. Howe KL, Achuthan P, Allen J, Allen J, Alvarez-Jarreta J, Amode MR, Armean IM, Azov AG, Bennett R, Bhai J, Billis K, Boddu S, Charkhchi M, Cummins C, Da Rin Fioretto L, Davidson C, Dodiya K, El Houdaigui B, Fatima R, Gall A, Garcia Giron C, Grego T, Guijarro-Clarke C, Haggerty L, Hemrom A, Hourlier T, Izuogu OG, Juettemann T, Kaikala V, Kay M, Lavidas I, Le T, Lemos D, Gonzalez Martinez J, Marugán JC, Maurel T, McMahon AC, Mohanan S, Moore B, Muffato M, Oheh DN, Paraschas D, Parker A, Parton A, Prosovetskaia I, Sakthivel MP, Salam AIA, Schmitt BM, Schuilenburg H, Sheppard D, Steed E, Szpak M, Szuba M, Taylor K, Thormann A, Threadgold G, Walts B, Winterbottom A, Chakiachvili M, Chaubal A, De Silva N, Flint B, Frankish A, Hunt SE, IIsley GR, Langridge N, Loveland JE, Martin FJ, Mudge JM, Morales J, Perry E, Ruffier M, Tate J, Thybert D, Trevanion SJ, Cunningham F, Yates AD, Zerbino DR, Flicek P. Ensembl 2021.. Nucleic Acids Res 2021 Jan 8;49(D1):D884-D891.
    pmc: PMC7778975pubmed: 33137190doi: 10.1093/nar/gkaa942google scholar: lookup
  24. Burns EN, Bordbari MH, Mienaltowski MJ, Affolter VK, Barro MV, Gianino F, Gianino G, Giulotto E, Kalbfleisch TS, Katzman SA, Lassaline M, Leeb T, Mack M, Müller EJ, MacLeod JN, Ming-Whitfield B, Alanis CR, Raudsepp T, Scott E, Vig S, Zhou H, Petersen JL, Bellone RR, Finno CJ. Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project.. Anim Genet 2018 Dec;49(6):564-570.
    pmc: PMC6264908pubmed: 30311254doi: 10.1111/age.12717google scholar: lookup
  25. Donnelly CG, Bellone RR, Hales EN, Nguyen A, Katzman SA, Dujovne GA, Knickelbein KE, Avila F, Kalbfleisch TS, Giulotto E, Kingsley NB, Tanaka J, Esdaile E, Peng S, Dahlgren A, Fuller A, Mienaltowski MJ, Raudsepp T, Affolter VK, Petersen JL, Finno CJ. Generation of a Biobank From Two Adult Thoroughbred Stallions for the Functional Annotation of Animal Genomes Initiative.. Front Genet 2021;12:650305.
    pmc: PMC7982670pubmed: 33763124doi: 10.3389/fgene.2021.650305google scholar: lookup
  26. Andrews S. A Quality Control Tool for High Throughput Sequence Data. FastQC; 2010.
  27. Ewels P, Magnusson M, Lundin S, Käller M. MultiQC: summarize analysis results for multiple tools and samples in a single report.. Bioinformatics 2016 Oct 1;32(19):3047-8.
  28. Martin M. Cutadapt removes adapter sequences from high‐throughput sequencing reads. EMBnetjournal 2011;17:10‐12.
  29. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform.. Bioinformatics 2009 Jul 15;25(14):1754-60.
  30. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. The Sequence Alignment/Map format and SAMtools.. Bioinformatics 2009 Aug 15;25(16):2078-9.
  31. Garrison E, Marth G. Haplotype‐based variant detection from short‐read sequencing. arXiv Preprint 2012;12073907.
  32. Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis.. Bioinformatics 2012 Sep 15;28(18):i333-i339.
  33. Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM, Lu X. Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift.. Front Genet 2012;3:35.
    pmc: PMC3304048pubmed: 22435069doi: 10.3389/fgene.2012.00035google scholar: lookup
  34. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, Land SJ, Lu X, Ruden DM. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.. Fly (Austin) 2012 Apr-Jun;6(2):80-92.
    pmc: PMC3679285pubmed: 22728672doi: 10.4161/fly.19695google scholar: lookup
  35. Peng S, Petersen JL, Bellone RR, Kalbfleisch T, Kingsley NB, Barber AM, Cappelletti E, Giulotto E, Finno CJ. Decoding the Equine Genome: Lessons from ENCODE.. Genes (Basel) 2021 Oct 27;12(11).
    pmc: PMC8625040pubmed: 34828313doi: 10.3390/genes12111707google scholar: lookup
  36. Kingsley NB, Kern C, Creppe C, Hales EN, Zhou H, Kalbfleisch TS, MacLeod JN, Petersen JL, Finno CJ, Bellone RR. Functionally Annotating Regulatory Elements in the Equine Genome Using Histone Mark ChIP-Seq.. Genes (Basel) 2019 Dec 18;11(1).
    pmc: PMC7017286pubmed: 31861495doi: 10.3390/genes11010003google scholar: lookup
  37. Peng S, Bellone R, Petersen JL, Kalbfleisch TS, Finno CJ. Successful ATAC-Seq From Snap-Frozen Equine Tissues.. Front Genet 2021;12:641788.
    pmc: PMC8242358pubmed: 34220931doi: 10.3389/fgene.2021.641788google scholar: lookup
  38. Tarasov A, Vilella AJ, Cuppen E, Nijman IJ, Prins P. Sambamba: fast processing of NGS alignment formats.. Bioinformatics 2015 Jun 15;31(12):2032-4.
  39. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, Liu XS. Model-based analysis of ChIP-Seq (MACS).. Genome Biol 2008;9(9):R137.
    pmc: PMC2592715pubmed: 18798982doi: 10.1186/gb-2008-9-9-r137google scholar: lookup
  40. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP. Integrative genomics viewer.. Nat Biotechnol 2011 Jan;29(1):24-6.
    pmc: PMC3346182pubmed: 21221095doi: 10.1038/nbt.1754google scholar: lookup
  41. Lavoie J, Hinchcliff KW. Blackwell's Five‐Minute Veterinary Consult: Equine. 2nd ed. Wiley‐Blackwell: Ames, IA; 2008.
  42. Lee DH, Gross MD, Jacobs DR Jr. Association of serum carotenoids and tocopherols with gamma-glutamyltransferase: the Cardiovascular Risk Development in Young Adults (CARDIA) Study.. Clin Chem 2004 Mar;50(3):582-8.
    pubmed: 14726472doi: 10.1373/clinchem.2003.028852google scholar: lookup
  43. Lee DH, Steffen LM, Jacobs DR Jr. Association between serum gamma-glutamyltransferase and dietary factors: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.. Am J Clin Nutr 2004 Apr;79(4):600-5.
    pubmed: 15051603doi: 10.1093/ajcn/79.4.600google scholar: lookup
  44. Lim JS, Yang JH, Chun BY, Kam S, Jacobs DR Jr, Lee DH. Is serum gamma-glutamyltransferase inversely associated with serum antioxidants as a marker of oxidative stress?. Free Radic Biol Med 2004 Oct 1;37(7):1018-23.
  45. Smith GW. Congenital Hyperbilirubinemia. In: Smith BP, van Metre DC, Pusterla N, eds. Large Animal Internal Medicine. 6th ed. St. Louis, MO: Elsevier; 2020:948.
  46. Owens D, Evans J. Population studies on Gilbert's syndrome.. J Med Genet 1975 Jun;12(2):152-6.
    pmc: PMC1013257pubmed: 1142378doi: 10.1136/jmg.12.2.152google scholar: lookup
  47. Black M, Billing BH. Hepatic bilirubin udp-glucuronyl transferase activity in liver disease and gilbert's syndrome.. N Engl J Med 1969 Jun 5;280(23):1266-71.
    pubmed: 5770050doi: 10.1056/nejm196906052802303google scholar: lookup
  48. ARIAS IM, LONDON IM. Bilirubin glucuronide formation in vitro; demonstration of a defect in Gilbert's disease.. Science 1957 Sep 20;126(3273):563-4.
    pubmed: 13467249doi: 10.1126/science.126.3273.563google scholar: lookup
  49. Fraitag S, Emile JF. Cutaneous histiocytoses in children.. Histopathology 2022 Jan;80(1):196-215.
    pubmed: 34958507doi: 10.1111/his.14569google scholar: lookup
  50. Wiles ET, Selker EU. H3K27 methylation: a promiscuous repressive chromatin mark.. Curr Opin Genet Dev 2017 Apr;43:31-37.
    pmc: PMC5447479pubmed: 27940208doi: 10.1016/j.gde.2016.11.001google scholar: lookup
  51. Leleu C, Haentjens F. Morphological, haemato-biochemical and endocrine changes in young Standardbreds with 'maladaptation' to early training.. Equine Vet J Suppl 2010 Nov;(38):171-8.
  52. Chanprasert S, Scaglia F. Adult liver disorders caused by inborn errors of metabolism: review and update.. Mol Genet Metab 2015 Jan;114(1):1-10.
    pubmed: 25467056doi: 10.1016/j.ymgme.2014.10.011google scholar: lookup

Citations

This article has been cited 0 times.