Skip to main content

Polymorphism of bovine beta-casein and its potential effect on human health

Abstract

Proteins in bovine milk are a common source of bioactive peptides. The peptides are released by the digestion of caseins and whey proteins. In vitro the bioactive peptide beta-casomorphin 7 (BCM-7) is yielded by the successive gastrointestinal proteolytic digestion of bovine beta-casein variants A1 and B, but this was not seen in variant A2. In hydrolysed milk with variant A1 of beta-casein, BCM-7 level is 4-fold higher than in A2 milk. Variants A1 and A2 of beta-casein are common among many dairy cattle breeds. A1 is the most frequent in Holstein-Friesian (0.310-0.660), Ayrshire (0.432-0.720) and Red (0.710) cattle. In contrast, a high frequency of A2 is observed in Guernsey (0.880-0.970) and Jersey (0.490-0.721) cattle. BCM-7 may play a role in the aetiology of human diseases. Epidemiological evidence from New Zealand claims that consumption of beta-casein A1 is associated with higher national mortality rates from ischaemic heart disease. It seems that the populations that consume milk containing high levels of beta-casein A2 have a lower incidence of cardiovascular disease and type 1 diabetes. BCM-7 has also been suggested as a possible cause of sudden infant death syndrome. In addition, neurological disorders, such as autism and schizophrenia, seem to be associated with milk consumption and a higher level of BCM-7. Therefore, careful attention should be paid to that protein polymorphism, and deeper research is needed to verify the range and natureof its interactions with the human gastrointestinal tract and whole organism.

This is a preview of subscription content, access via your institution.

References

  1. A2 Corporation, 2006. http://www.a2corporation.com/in-dex.php/ps_ pagename /corporate.

  2. Baranyi M, Bosze Z, Buchberger J, Krause I, 1997. Genetic polymorphism of milk proteins in Hungarian cattle breeds and PCR amplification of betalactoglobulin exon 5 to identify genetic variant J by RFLP. In: Milk protein polymorphism. Proceedings of the IDF Seminar held in Palmerston North, New Zealand. Int Dairy Fed: 87–92.

  3. Bech AM, Kristiansen KR, 1990. Milk protein polymorphism in Danish dairy cattle and the influence of genetic variants on milk yield. J Dairy Res 57: 53–62.

    CAS  Article  PubMed  Google Scholar 

  4. Bell SJ, Grochoski GT, Clarke AJ, 2006. Health implications of milk containing beta-casein with the A2 genetic variant. Crit Rev Food Sci Nutr 46: 93–100.

    CAS  Article  PubMed  Google Scholar 

  5. Birgisdottir BE, Hill JP, Thorsson AV, Thorsdottir I, 2006. Lower consumption of cow milk protein A1 beta-casein at 2 years of age, rather than consumption among 11- to 14-year-old adolescents, may explain the lower incidence of type 1 diabetes in Iceland than in Scandinavia. Ann Nutr Metab 50: 177–183.

    CAS  Article  PubMed  Google Scholar 

  6. Brantl V, Teschemacher H, Henschen A, Lottspeich F, 1979. Novel opioid peptides derived from casein (b-casomorphins). I. Isolation from bovine casein peptone. Hoppe Seylers Z Physiol Chem 360: 1211–1216.

    CAS  PubMed  Google Scholar 

  7. Brooks JG, 1982. Apnea of infancy and sudden infant death syndrome. Am J Dis Child 136: 1012–1023.

    CAS  PubMed  Google Scholar 

  8. Cade R, Privette R, Fregly M, Rowland N, Sun Z, Zele V, 2000. Autism and schizophrenia: intestinal disorders. Nutr Neurosci 3: 57–72.

    Google Scholar 

  9. Cavallo MG, Monetini L, Walker BK, Thorpe R, Pozzilli P, 1996. Diabetes and cows’ milk. Lancet 348: 1655.

    Article  Google Scholar 

  10. Chang KJ, Su YF, Brent DA, Chang JK, 1985. Isolation of a specific m-opiate receptor peptide, morphiceptin, from an enzymatic digest of milk proteins. Biol Chem 260: 9706–9712.

    CAS  Google Scholar 

  11. Chatchatee P, Jarvinen KM, Bardina L, Vila L, Beyer K, Sampson HA, 2001a. Identification of IgE and IgG binding epitopes on beta- and kappa-casein on cow’s milk allergic patients. Clin Exp Allergy 31: 1256–1265.

    CAS  Article  PubMed  Google Scholar 

  12. Chatchatee P, Jarvinen KM, Bardina L, Vila L, Beyer K, Sampson HA, 2001b. Identification of IgE and IgG binding epitopes on alpha(s1)-casein: differences in patients with persistent and transient cow’s milk allergy. J Allergy Clin Immunol 107: 379–383.

    CAS  Article  PubMed  Google Scholar 

  13. Chessa S, Chiatti F, Ceriotti G, Caroli A, Consolandi C, Pagnacco G, Castiglioni B, 2007. Development of a single nucleotide polymorphism genotyping microarray platform for the identification of bovine milk protein genetic polymorphisms. J Dairy Sci 90: 451–464.

    CAS  Article  PubMed  Google Scholar 

  14. Cieślińska A, Kamiński S, Kostyra E, Sienkiewicz-Szłapka E, 2007. Beta-casomorphin 7 in raw and hydrolysed milk derived from cows of alternative -casein genotypes. Milchwissenschaft 62: 125–127.

    Google Scholar 

  15. Curik I, Havranek J, Samarzija D, 1997. Milk protein polymorphism and genetic structure of Croatian Simmental cattle. In: Milk protein polymorphism. Proceedings of the IDF Seminar held in Palmerston North, New Zealand. Int Dairy Fed: 93–99.

  16. Eenennam A, Medrano JF, 1991. Milk protein polymorphism in California dairy cattle. J Dairy Sci 74: 1730–1742.

    Article  Google Scholar 

  17. Ehrmann S, Bartenschlager H, Geldermann H, 1997. Quantification of gene effects on single milk proteins in selected groups of dairy cows. J Anim Breed Genet 114: 121–132.

    CAS  Google Scholar 

  18. Eigel WN, Butler JE, Ernstrom CA, Farrell HM, Halwarkar VR, Jenness R, Whitney RM, 1984. Nomenclature of proteins of cow’s milk: fifth revision. J Dairy Sci 67: 1599–1631.

    CAS  Article  Google Scholar 

  19. Elliott RB, Wasmuth HE, Bibby NJ, Hill JP, 1997. The role of beta-casein variants in the induction of insulin-dependent diabetes in the non-obese diabetic mouse and humans. In: Milk protein polymorphism. Proceedings of the IDF Seminar held in Palmerston North, New Zealand. Int Dairy Fed: 445–453.

  20. Elliott RB, Harris DP, Hill JP, Bibby NJ, Wasmuth HE, 1999. Type I (insulindependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia 42: 292–296.

    CAS  Article  PubMed  Google Scholar 

  21. Farrell HM Jr, Jimenez-Flores R, Bleck GT, Brown EM, Butler JE, Creamer LK, et al. 2004. Nomenclature of the proteins of cows’ milk-sixth revision. J Dairy Sci 87: 1641–1674.

    CAS  Article  PubMed  Google Scholar 

  22. Gill HS, Doull F, Rutherfurd KJ, Cross ML, 2000. Immunoregulatory peptides in bovine milk. Br J Nutr 84: 111–117.

    Google Scholar 

  23. Groves ML, 1969. Some minor components of casein and other phosphoproteins in milk. A review. J Dairy Sci 52: 1155–1165.

    CAS  Article  Google Scholar 

  24. Gobbetti M, Stepaniak L, De Angelis M, Corsetti A, Di Cagno R, 2002. Latent bioactive peptides in milk proteins: proteolytic activation and significance in dairy processing. Crit Rev Food Sci Nutr 42: 223–239.

    CAS  Article  PubMed  Google Scholar 

  25. Hartwig A, 1997. Einfluss genetischer Varianten bovinen beta-Caseins auf Entstehung und Aktivitat biologisch aktiver Peptide. Dissertation im Fachbereich Ernahrungs- und Haushaltswissenschaften, Justus-Liebig-Universitat Gießen. ??

  26. Hartwig A, Teschemacher H, Lehmann W, Gauly M, Erhardt G, 1997. Influence of genetic polymorphisms in bovine milk on the occurrence of bioactive peptides. In: Milk protein polymorphism. Proceedings of the IDF Seminar held in Palmerston North, New Zealand. Int Dairy Fed: 459–460.

  27. Heinecke JW, 1999. Mass spectrometric quantification of amino acid oxidation products in proteins: insights into pathways that promote LDL oxidation in the human artery wall. FASEB J 13: 1113–1120.

    CAS  PubMed  Google Scholar 

  28. Ikonen T, Ojala M, Ruottinen O, 1997. Effects of beta- and kappa-casein genotypes on first lactation milk production traits in Finnish Ayrshire cows. In: Milk protein polymorphism. Int Dairy Fed: 47–53.

  29. Jarmołowska B, Kostyra E, Krawczuk S, Kostyra H, 1999. Beta-casomorphin-7 isolated from Brie cheese. J Sci Food Agric 79: 1788–1792.

    Article  Google Scholar 

  30. Jarmołowska B, Bielikowicz K, Iwan M, Sidor K, Kostyra E, Kaczmarski M, 2007. Serum activity of dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) in breast-fed infants with symptoms of allergy. Peptides 28: 678–682.

    Article  PubMed  Google Scholar 

  31. Jinsmaa Y, Yoshikawa M, 1999. Enzymatic release of neocasomorphin and beta-casomorphin from bovine beta-casein. Peptides V 20: 957–962.

    CAS  Article  Google Scholar 

  32. Kamiński S, Ahman A, Ruść A, Wójcik A, Malewski T, 2005. MilkProtChip - a microarray of SNPs in candidate genes associated with milk protein biosynthesis - development and validation. J Appl Genet 46: 45–58.

    PubMed  Google Scholar 

  33. Kamiński S, Ruść A, Cieślińska A, 2006a. A note on frequency of A1 and A2 variants of bovine beta-casein locus in Polish Holstein bulls. J Anim Feed Sci 15: 195–198.

    Google Scholar 

  34. Kamiński S, Brym P, Ruść A, Wójcik E, Ahman A, Magi R, 2006b. Associations between milk performance traits in Holstein cows and 16 candidate SNPs identified by arrayed primer extension (APEX) microarray. Anim Biotechnol 17: 1–11.

    Article  PubMed  Google Scholar 

  35. Korhonen H, Pihlanto-Leppala A, Rantamaki P, Tupasela T, 1998. Impact of processing on bioactive proteins and peptides. Trends Food Sci Technol 9: 307–319.

    CAS  Article  Google Scholar 

  36. Kostyra E, Kostyra H, Jarmołowska B, Krawczuk S, 2002.Tetrahymena termophila as a source of the opioid receptors for testing of opioid peptides. Pol J Environ Stud 11: 707–712

    CAS  Google Scholar 

  37. Kostyra E, Sienkiewicz-Szłapka E, Jarmołowska B, Krawczuk S, Kostyra H, 2004. Opioid peptides derived from milk proteins. Pol J Nutr Sci 13/54: 25–35.

    Google Scholar 

  38. Kreil G, Umbach M, Brantl V, Teschmacher H, 1983. Study on the enzymatic degradation of betacasomorphin. Life Sci 33: 137–140.

    CAS  Article  PubMed  Google Scholar 

  39. Kurek M, Przybilla B, Hermann K, Ring J, 1992. A naturally occurring opioid peptide from cow’s milk, beta-casomorphine-7, is a direct histamine releaser in man. Int Arch Allergy Immunol 97: 115–120.

    CAS  Article  PubMed  Google Scholar 

  40. Lambeir AM, Durinx C, Scharpe S, De Meester I, 2003. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 40: 209–294.

    CAS  Article  PubMed  Google Scholar 

  41. Laugesen M, Elliott R, 2003. Ischaemic heart disease, type 1 diabetes, and cow milk A1 beta-casein. N Z Med J 116: 1–19.

    Google Scholar 

  42. Lien S, Rogne S, 1993. Bovine casein haplotypes: number, frequencies and applicability as genetic markers. Anim Genet 24: 373–376.

    CAS  Article  PubMed  Google Scholar 

  43. Lindstrome LH, Nyberg F, Terenius L, Baure K, Besev G, Gunne LM, 1984. CSF and plasma beta-casomorphin-like opioidpeptides in postpartum psychosis. Am J Psychiatry 141: 1059–1066.

    Google Scholar 

  44. Lunden A, Nilsson M, Janson L, 1997. Marked effect of beta-lactoglobulin polymorphism on the ratio of case in to total protein in milk. J Dairy Sci 80: 2996–3005.

    CAS  Article  PubMed  Google Scholar 

  45. Martien AM, Groenen J, van der Poel J, 1994. Regulation of expression of milk protein genes: a review. Livest Prod Sci 38: 61–78.

    Article  Google Scholar 

  46. McLachlan CN, 2001. Beta-casein A1, ischaemic heart disease mortality, and other illnesses. Med Hypotheses 56: 262–272.

    CAS  Article  PubMed  Google Scholar 

  47. Meisel H, 1997. Biochemical properties of regulatory peptides derived from milk proteins. Biopolymers 43: 119–128.

    CAS  Article  PubMed  Google Scholar 

  48. Meisel H, Bockelmann W, 1999. Bioactive peptides encrypted in milk proteins: proteolytic activation and thropho-functional properties. Antonie Van Leeuwenhoek 76: 207–215.

    CAS  Article  PubMed  Google Scholar 

  49. Meisel H, Fitzgerald RJ, 2000. Opioid peptides encrypted in intact milk protein sequences. Br J Nutr 84: 27–31.

    Article  Google Scholar 

  50. Miller MJS, Witherly SA, Clark DA, 1990. Casein: a milk protein with diverse biologic consequences. Proc Soc Exp Biol Med 195: 143–159.

    CAS  PubMed  Google Scholar 

  51. Muehlenkamp MR, Warthesen JJ, 1996. Betacasomorphins: analysis in cheese and susceptibility to proteolytic enzyme fromLactococcus lactis ssp.cremoris. J Dairy Sci 79: 20–26.

    CAS  Article  PubMed  Google Scholar 

  52. Niki R, Kim GY, Kimura T, Takahashi K, Koyama K, Nishinari K, 1994. Physical properties and microstructure of rennet gels from casein micelles of different sizes. Milchwissenschaft 49: 325–329.

    CAS  Google Scholar 

  53. Norris CS, Coker CJ, Boland MJ, Hill JP, 2003. Analysis of the water-soluble fraction of a selection of cheeses for beta-casomorphin, its precursors and its analogues. Aust J Dairy Technol 58: 201.

    Google Scholar 

  54. Ostersen S, Foldaber J, Hermansen JE, 1997. Effects of stage of lactation, milk protein genotype and body condition at calving on protein composition and renneting properties of bovine milk. J Dairy Res 64: 207–219.

    CAS  Article  PubMed  Google Scholar 

  55. Ramabadran K, Bansinath M, 1989. Pharmacology of beta-casomorphins, opioid peptides derived from milk protein. Asia Pac J Pharmacol 4: 45–58.

    CAS  Google Scholar 

  56. Reichelt KL, Krem J, Scott H, 1990. Gluten, milk proteins and autism: dietary intervention effects on behavior and peptide secretion. J Appl Nutrition 42: 1–11

    Google Scholar 

  57. Reichelt KL, Knivsberg AM, Lind G, Nodland M, 1991. Probable etiology and possible treatment of childhood autism. Brain Dysfunction 4: 308–319.

    Google Scholar 

  58. Rijnkels M, 2002. Multispecies comparison of the casein gene loci and evolution of casein gene family. J Mammary Gland Biol Neoplasia 7: 327–345.

    Article  PubMed  Google Scholar 

  59. Roginski H, 2003. Encyclopedia of dairy sciences. Academic Press, London.

    Google Scholar 

  60. Sturner RA, Chang KJ, 1988. Opioid peptide content in infant formulas. Pediatr Res 23: 4–10.

    Google Scholar 

  61. Sun Z, Zhang Z, Wang X, Cade R, Elmer Z, Fregly M, 2003. Relation of beta-casomorphin to apnea in sudden infant death syndrome. Peptides 24: 937–943.

    CAS  Article  PubMed  Google Scholar 

  62. Swaissgood HE, 1992. Chemistry of the caseins. Advanced dairy chemistry-1: proteins. Fox PF, Elsevier, London: 63–77.

    Google Scholar 

  63. Tailford KA, Berry CL, Thomas AC, Campbell JH, 2003. A casein variant in cow’s milk is atherogenic. Atherosclerosis 170: 13–19.

    CAS  Article  PubMed  Google Scholar 

  64. Teschemacher H, 2003. Opioid receptor ligands derived from food proteins. Curr Pharm Des 9: 1331–1344.

    CAS  Article  PubMed  Google Scholar 

  65. Thorsdottir I, Birgisdottir BE, Johannsdottir IM, Harris P, 2000. Different (beta-casein) fractions in Icelandic versus Scandinavian cow’s milk may influence diabetogenicity of cow’s milk in infancy and explain low incidence of insulin-dependent diabetes mellitus in Iceland. Pediatrics 106: 719–724.

    CAS  Article  PubMed  Google Scholar 

  66. Truswell AS, 2005. The A2 milk case: a critical review. Eur J Clin Nutr 59: 623–631.

    CAS  Article  PubMed  Google Scholar 

  67. Winkelman AM, Wickham BW, 1997. Associations between milk protein genetic variants and production traits in New Zealand dairy cattle. In: Milk protein polymorphism. Proceedings of the IDF Seminar held in Palmerston North, New Zealand. Int Dairy Fed: 38–46.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Stanisław Kamiński.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kamiński, S., Cieślińska, A. & Kostyra, E. Polymorphism of bovine beta-casein and its potential effect on human health. J Appl Genet 48, 189–198 (2007). https://doi.org/10.1007/BF03195213

Download citation

Keywords

  • beta-casein
  • beta-casomorphin 7
  • diabetes
  • ischaemic heart disease
  • polymorphism