Journal of Genetics

, Volume 97, Issue 5, pp 1147–1154 | Cite as

Polymorphisms in toll-like receptor (TLR) 1, 4, 9 and SLC11A1 genes and their association with paratuberculosis susceptibility in Holstein and indigenous crossbred cattle in Turkey

  • Mehmet Ulas CinarEmail author
  • Harun Hizlisoy
  • Bilal Akyüz
  • Korhan Arslan
  • Esma Gamze Aksel
  • Kadir Semih Gümüşsoy
Research Article


Mycobacterium avium subsp. paratuberculosis (MAP) causes major problem in a wide range of animal species. In ruminant livestock including cattle, it causes a chronic disease called Johne’s disease, or paratuberculosis (pTB) which is currently considered as potential zoonosis, causing Crohn’s disease in humans. MAP infection susceptibility is suspected to be controlled by host genetics. Thus, selecting individuals according to their genetic structure could help to obtain bovine populations that are increasingly resistant to MAP infection. The aim of the present work was to investigate the association between toll-like receptor (TLR) \({ 1}\) (+1380 G/A), TLR1 (+1446 C/A), TLR4 (+10 C/T), TLR9 (+1310 G/A) and solute carrier family 11 member 1 (SLC11A1) (+1066 C/G) mutations and MAP infection status in 813 cattle comprising East Anatolian Red crossbred, Anatolian Black crossbred and Holstein breed. TLR1 (+1380 G/A) mutation showed an association with bovine MAP (\(P\!<\!0.05\)). For the TLR1 (+1380 G/A) locus, the odds ratio for AG and AA genotypes versus GG genotypes were 2.31 (1.24–4.30; 95% confidence interval (CI)) and 0<0.001 (<0.001 to >999.999; 95% CI) which indicated that a proportion of AG homozygote was significantly higher in pTB-affected animals as compared with the control. General linear model analysis demonstrated higher MAP antibody response in TLR1 (+1380 AG) genotype as compared with TLR1 (+1380 GG) (\(P\!<\! 0.0001\)). Present findings suggest that selection against TLR1 (+1380 G/A) may reduce the risk of pTB in bovine herds.


Johne’s disease bovine genetics disease risk anatolian indigenous cattle 



This research was financially supported by the Turkish Research Council (TUBITAK) grant number 115O478.

Supplementary material

12041_2018_1008_MOESM1_ESM.doc (89 kb)
Supplementary material 1 (doc 89 KB)


  1. Akira S., Takeda K. and Kaisho T. 2001 Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680.CrossRefGoogle Scholar
  2. Arpaia N, Godec J, Lau L, Sivick K. E., McLaughlin L. M., Jones M. B. et al. 2011 TLR signaling is required for Salmonella typhimurium virulence. Cell 144, 675–688.CrossRefGoogle Scholar
  3. Bishop S. C. 2015 Genetic resistance to infections in sheep. Vet. Microbiol. 181, 2–7.CrossRefGoogle Scholar
  4. Bishop S. C. and Woolliams J. A. 2014 Genomics and disease resistance studies in livestock. Livest. Sci. 166, 190–198.CrossRefGoogle Scholar
  5. Blackwell J. M., Goswami T., Evans, C. A. W., Sibthorpe D., Papo N., White J. K. et al. 2001 SLC11A1 (formerly NRAMP1) and disease resistance. Cell. Microbiol. 3, 773–784.CrossRefGoogle Scholar
  6. Cetinkaya B., Erdogan H. M. and Morgan K. L. 1997 Relationships between the presence of Johne’s disease and farm and management factors in dairy cattle in England. Prev. Vet. Med. 32, 253–266.CrossRefGoogle Scholar
  7. Chaubey K. K., Gupta R. D., Gupta S., Singh S. V., Bhatia A. K., Jayaraman S. et al. 2016 Trends and advances in the diagnosis and control of paratuberculosis in domestic livestock. Vet. Q. 36, 203–227.CrossRefGoogle Scholar
  8. Cho J., Tauer L. W., Schukken Y. H., Gómez M. I. Smith R. L., Lu Z. et al. 2012 Economic analysis of Mycobacterium avium subspecies paratuberculosis vaccines in dairy herds. J. Dairy Sci. 95, 1855–1872.CrossRefGoogle Scholar
  9. Collins M. T. 2011 Diagnosis of paratuberculosis. Vet. Clin. North Am. Food Anim. Pract. 27, 581–591.CrossRefGoogle Scholar
  10. Elzo M. A., Rae D. O., Lanhart S. E., Wasdin J. G., Dixon W. P. and Jones J. L. 2006 Factors associated with ELISA scores for paratuberculosis in an Angus-Brahman multibreed herd of beef cattle. J. Anim. Sci. 84, 41–48.CrossRefGoogle Scholar
  11. Fecteau M. E. 2018 Paratuberculosis in cattle. Vet. Clin. North Am. Food Anim. Pract. 34, 209–222.CrossRefGoogle Scholar
  12. Fisher C. A., Bhattarai E. K., Osterstock J. B., Dowd S. E., Seabury P. M., Vikram M. et al. 2011 Evolution of the bovine TLR gene family and member associations with Mycobacterium avium subspecies paratuberculosis infection. PLoS One 6, e27744.CrossRefGoogle Scholar
  13. Hinger M., Brandt H. and Erhardt G. 2008 Heritability estimates for antibody response to Mycobacterium avium subspecies paratuberculosis in German Holstein cattle. J. Dairy Sci. 91, 3237–3244.CrossRefGoogle Scholar
  14. Juste R. A. 2012 Current strategies for eradication of paratuberculosis and issues in public health. Vet. Immunol. Immunopathol. 148, 16–22.CrossRefGoogle Scholar
  15. Kirkpatrick B. W. and Shook G. E. 2011 Genetic susceptibility to paratuberculosis. Vet. Clin. North Am. Food Anim. Pract. 27, 559–571.CrossRefGoogle Scholar
  16. Kirkpatrick B. W., Shi X., Shook G. E. and Collins M. T. 2011 Whole-genome association analysis of susceptibility to paratuberculosis in Holstein cattle. Anim. Genet. 42, 149–160.CrossRefGoogle Scholar
  17. Koets A., Santema W., Mertens H., Oostenrijk D., Keestra M., Overdijk M. et al. 2010 Susceptibility to paratuberculosis infection in cattle is associated with single nucleotide polymorphisms in Toll-like receptor 2 which modulate immune responses against Mycobacterium avium subspecies paratuberculosis. Prev. Vet. Med. 93, 305–315.CrossRefGoogle Scholar
  18. Lin B. Z., Sasazaki S. and Mannen H. 2010 Genetic diversity and structure in Bos taurus and Bos indicus populations analyzed by SNP markers. Anim. Sci. J. 81, 281–289.CrossRefGoogle Scholar
  19. Marcé C., Ezanno P., Weber M. F., Seegers H., Pfeiffer D. U. and Fourichon C. 2010 Invited review: modeling within-herd transmission of Mycobacterium avium subspecies paratuberculosis in dairy cattle: a review. J. Dairy Sci. 93, 4455–4470.CrossRefGoogle Scholar
  20. Meuwissen T., Hayes B. and Goddard M. 2013 Accelerating improvement of livestock with genomic selection. Annu. Rev. Anim. Biosci. 1, 221–237.CrossRefGoogle Scholar
  21. Misch E. A., Macdonald M., Ranjit C., Sapkota B. R., Wells R. D., Siddiqui M. R. et al. 2008 Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Neglected Trop. Dis. 2, e231.CrossRefGoogle Scholar
  22. Mortensen H., Nielsen S. S. and Berg P. 2004 Genetic variation and heritability of the antibody response to Mycobacterium avium subspecies paratuberculosis in Danish Holstein cows. J. Dairy Sci. 87, 2108–2113.CrossRefGoogle Scholar
  23. Mucha R., Bhide M. R., Chakurkar E. B., Novak M. and Mikula I. 2009 Toll-like receptors TLR1, TLR2 and TLR4 gene mutations and natural resistance to Mycobacterium avium subsp. paratuberculosis infection in cattle. Vet. Immunol. Immunopathol. 128, 381–388.CrossRefGoogle Scholar
  24. Nielsen D. M. and Weir B. S. 2001 Association studies under general disease models. Theor. Popul. Biol. 60, 253–263.CrossRefGoogle Scholar
  25. Pinedo P. J., Buergelt C. D., Donovan G. A., Melendez P., Morel L., Wu R. et al. 2009 Candidate gene polymorphisms (BoIFNG, TLR4, SLC11A1) as risk factors for paratuberculosis infection in cattle. Prev. Vet. Med. 91, 189–196.CrossRefGoogle Scholar
  26. Pinedo P. J., Galvão K. N. and Seabury C. M. 2013 Innate immune gene variation and differential susceptibility to uterine diseases in Holstein cows. Theriogenology 80, 384–390.CrossRefGoogle Scholar
  27. Prakash O., Kumar A., Sonwane A., Rathore R., Singh R. V., Chauhan A. et al. 2014 Polymorphism of cytokine and innate immunity genes associated with bovine brucellosis in cattle. Mol. Biol. Rep. 41, 2815–2825.CrossRefGoogle Scholar
  28. Randhawa I. A. S., Khatkar M. S., Thomson P. C. and Raadsma H. W. 2016 A meta-assembly of selection signatures in cattle. PLoS One 11, e0153013.CrossRefGoogle Scholar
  29. Roussel A. J., Libal M. C., Whitlock R. L., Hairgrove T. B., Barling K. S. and Thompson J. A. 2005 Prevalence of and risk factors for paratuberculosis in purebred beef cattle. J. Am. Vet. Med. Assoc. 226, 773–778.CrossRefGoogle Scholar
  30. Ruiz-Larrañaga O., Garrido J. M., Manzano C., Iriondo M., Molina E., Gil A. et al. 2010 Identification of single nucleotide polymorphisms in the bovine solute carrier family 11 member 1 (SLC11A1) gene and their association with infection by Mycobacterium avium subspecies paratuberculosis. J. Dairy Sci. 93, 1713–1721.CrossRefGoogle Scholar
  31. Ruiz-Larrañaga O., Manzano C., Iriondo M., Garrido J. M., Molina E., Vazquez P. et al. 2011 Genetic variation of toll-like receptor genes and infection by Mycobacterium avium ssp. paratuberculosis in Holstein-Friesian cattle. J. Dairy Sci. 94, 3635–3641.CrossRefGoogle Scholar
  32. Smith R. L., Al-Mamun M. A. and Gröhn, Y. T. 2017 Economic consequences of paratuberculosis control in dairy cattle: a stochastic modeling study. Prev. Vet. Med. 138, 17–27.CrossRefGoogle Scholar
  33. Sun L., Song Y., Riaz H., Yang H., Hua G., Guo A. et al. 2012 Polymorphisms in toll-like receptor 1 and 9 genes and their association with tuberculosis susceptibility in Chinese Holstein cattle. Vet. Immunol. Immunopathol. 147, 195–201.CrossRefGoogle Scholar
  34. Sweeney R. W., Collins M. T., Koets A. P., McGuirk S. M. and Roussel A. J. 2012 Paratuberculosis (Johne’s disease) in cattle and other susceptible species. J. Vet. Intern. Med. 26, 1239–1250.CrossRefGoogle Scholar
  35. Takeda K. and Akira S. 2005 Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14.CrossRefGoogle Scholar
  36. Takeda K., Takeuchi O. and Akira S. 2002 Recognition of lipopeptides by toll-like receptors. J. Endotoxin Res. 8, 459–463.CrossRefGoogle Scholar
  37. Taylor K. H., Taylor J. F., White S. N. and Womack J. E. 2006 Identification of genetic variation and putative regulatory regions in bovine CARD15. Mamm. Genome 17, 892–901.CrossRefGoogle Scholar
  38. Tewari D., Hovingh E., Linscott R., Martel E., Lawrence J., Wolfgang D. et al. 2014 Mycobacterium avium subsp. paratuberculosis antibody response, fecal shedding, and antibody cross-reactivity to Mycobacterium bovis in M. avium subsp. paratuberculosis-infected cattle herds vaccinated against Johne’s disease. Clin. Vaccine Immunol. 21, 698–703.CrossRefGoogle Scholar
  39. Trangoni M. D., Gioffré A. K., Cerón Cucchi M. E., Caimi K. C., Ruybal P., Zumárraga M. J. et al. 2015 LAMP technology: rapid identification of Brucella and Mycobacterium avium subsp. paratuberculosis. Braz. J. Microbiol. 46, 619–626.Google Scholar
  40. Vordermeier M., Ameni G., Berg S., Bishop R., Robertson B. D., Aseffa A. et al. 2012 The influence of cattle breed on susceptibility to bovine tuberculosis in Ethiopia. Comp. Immunol. Microbiol. Infect. Dis. 35, 227–232.CrossRefGoogle Scholar
  41. Wentink G. H., Bongers J. H., Zeeuwen A. A. and Jaartsveld F. H. 1994 Incidence of paratuberculosis after vaccination against M. paratuberculosis in two infected dairy herds. Zentralbl. Vet. B 41, 517–522.Google Scholar
  42. Werling D., Jann O. C., Offord V., Glass E. J. and Coffey T. J. 2009 Variation matters: TLR structure and species-specific pathogen recognition. Trends Immunol. 30, 124–130.CrossRefGoogle Scholar
  43. White S. N., Taylor K. H., Abbey C. A., Gill C. A. and Womack J. E. 2003 Haplotype variation in bovine Toll-like receptor 4 and computational prediction of a positively selected ligand-binding domain. Proc. Natl. Acad. Sci. U.S.A. 100, 10364–10369.CrossRefGoogle Scholar
  44. Wiersinga W. J., Wieland C. W., Dessing M. C., Chantratita N., Cheng A. C., Limmathurotsakul D. et al. 2007 Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis). PLoS Med. 4, e248.Google Scholar
  45. Yap G. S., Shaw M. H., Ling Y. and Sher A. 2006 Genetic analysis of host resistance to intracellular pathogens: lessons from studies of Toxoplasma gondii infection. Microbes Infect. 8, 1174–1188.CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  • Mehmet Ulas Cinar
    • 1
    Email author
  • Harun Hizlisoy
    • 2
  • Bilal Akyüz
    • 3
  • Korhan Arslan
    • 3
  • Esma Gamze Aksel
    • 3
  • Kadir Semih Gümüşsoy
    • 4
  1. 1.Faculty of Agriculture, Department of Animal ScienceErciyes UniversityKayseriTurkey
  2. 2.Faculty of Veterinary Medicine, Department of Veterinary Public HealthErciyes UniversityKayseriTurkey
  3. 3.Faculty of Veterinary Medicine, Department of GeneticsErciyes UniversityKayseriTurkey
  4. 4.Faculty of Veterinary Medicine, Department of MicrobiologyErciyes UniversityKayseriTurkey

Personalised recommendations