Beta casein A1 and A2 in milk and human health

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Research

Scientific studies pointing to potential health effects of the various beta casein types have generated wide international interest and research is ongoing as to how the beta casein variants can affect our health.

A summary of research behind beta casein “Beta casein A1 and A2 in milk and human health” concluded:

“The A1/A2 hypothesis is both intriguing and potentially very important for population health if it is proved correct. It should be taken seriously and further research is needed”.

Key research including population, human and animal studies can be found referenced below.

Childhood (Type 1) Diabetes
Epidemiological (Population) studies
Drinking milk high in A2 beta casein at 2 yrs of age was linked to a lower risk of childhood diabetes in Iceland and Scandinavia. Drinking milk containing A1 casein in early childhood was linked with diabetes.	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 rate of type 1 diabetes in Iceland than in Scandinavia. Birgisdottir BE, Hill JP, Thorsson AV, Thorsdottir I. (2006) Ann Nutr Metab. 50(3):177-83.
Drinking milk high in A2 beta casein is linked to a lower risk of childhood diabetes in Icelandic children. The low rate of diabetes in Iceland was linked to their milk containing less A1 beta casein compared to other Nordic countries showing that lower consumption of A1 decreases rates of diabetes.	Variation in consumption of cow milk proteins and lower rate of Type 1 diabetes in Iceland versus the other 4 Nordic countries. Birgisdottir BE, Hill JP, Harris DP, Thorsdottir I. 2002. Diabetes Nutr. Metab. 15 (4) 240-245
Across 20 countries beta casein A1 consumption is shown to be strongly associated with rates of diabetes concluding that milk high in A2 beta casein may lower the risk of childhood diabetes.	Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein. Laugesen M & Elliott R, 2003. New Zealand Medical Journal 116(1168) U295.
Drinking milk high in A2 beta casein in childhood may lower the risk of childhood diabetes. Drinking milk higher in beta casein A1 is strongly linked to the rate of childhood diabetes in 0-14 year olds.	beta-casein A1, ischaemic heart disease mortality, and other illnesses. McLachlan, C. N. S. 2001. beta-casein A1, Medical Hypotheses. 56(2), 262-272
Low amounts of A1 beta casein in Icelandic cows’ milk is linked to the lower childhood diabetes rate in Iceland compared to the rest of Scandinavia.	Different beta-casein fractions in Icelandic versus Scandinavian cow’s milk may influence diabetogenicity of cow’s milk in infancy and explain low rate of insulin-dependent diabetes mellitus in Iceland. Thorsdottir I, Birgisdottir BE, Johannsdottir IM, Harris DP, Hill J, Steingrimsdottir L, Thorsson A (2000) Pediatrics 106(4):719-24
A strong link was shown between A1 beta casein and the rate of childhood diabetes across different German states. This shows that higher A1 consumption is linked to increased rates of childhood diabetes.	b-casein A1 consumption and incidence of Type 1 Diabetes in Germany. Wasmuth, H.E., Rosenbauer, J., Elliott, RB., Mclachlan, C., Erhardt, G., Giani, G., Kolb, H.: Kongress der Europäischen Diabetesgesellschaft vom 28.-30.09.1999 in Brüssel/Belgien (Conference Presentation)
A1 beta casein is linked to the rate of childhood diabetes, but A2 is not. The consumption of A1 beta casein was found to correspond with the rate of childhood diabetes in children age 0-14 years, showing a linkage between A1 consumption and rate of childhood diabetes	Type 1 (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption Elliott RB, Harris DP, Hill JP, Bibby NJ, Wasmuth HE. 1999.. Diabetologia 42 (3)292-296.
Human studies
Antibodies to A1 beta casein were detected in type 1 diabetes patients whereas antibodies to A2 beta casein were present in ‘control’ patients. This supports the link between A1 consumption and childhood diabetes	[The significance of A1 and A2 antibodies against beta-casein in type-1 diabetes mellitus]. Padberg S, Schumm-Draeger PM, Petzoldt R, Becker F, Federlin K. 1999. (Article in German.) Dtsch Med Wochenschr. 124 (50) 1518-21.
High levels of antibodies to beta casein were found in the blood of patients with childhood diabetes, adult latent autoimmune diabetes and coeliac disease linking beta casein to these diseases	Antibodies to bovine beta-casein in diabetes and other autoimmune diseases Monetini L, Cavallo MG, Manfrini S, Stefanini L, Picarelli A, Di Tola M, Petrone A, Bianchi M, La Presa M, Di Giulio C, Baroni MG, Thorpe R, Walker BK, Pozzilli P (2002). Horm Metab Res. 34 (8) 455-9.
Breast feeding for the first 4 months was shown to prevent antibody (immune) response to cow beta casein (linked to childhood diabetes)	Bovine beta-casein antibodies in breast- and bottle-fed infants: their relevance in Type 1 diabetes. Monetini L, Cavallo MG, Stefanini L, Ferrazzoli F, Bizzarri C, Marietti G, Curro V, Cervoni M, Pozzilli (2001) P. Diabetes Metab Res Rev. 17(1):51-4
Those with childhood diabetes had an immune response towards beta casein. This is evidence that beta casein could be a environmental trigger for genetically susceptible individuals to develop childhood diabetes.	Beta-casein in cow’s milk: A major antigenic determinant for type 1 diabetes? Pozzilli P. 1999. Journal of Endocrinological Investigations 22 (7) 562-567
Other research
BCM7 was linked to childhood diabetes	The role of ß-casein variants in the induction of insulin-dependent diabetes in the non-obese diabetic mouse and humans. Elliott RB, Wasmuth HE, Bibby NJ, Hill JP: Seminar on milk protein polymorphism, IDF special issue no. 9702. International Dairy Federation, Brussels, 445–453, 1997
Beta casomorphins affect the function of the pancreas, the site of insulin production	Influence of b-casomorphins on the function of the endocrine pancreas: ß-Casomorphins and Related Peptides: Recent Developments. Zuhlke H. Damert A. Eckhardt W. Hubner G. Kauschke R. Salazar R. Neubert K. (Brantl V. and Teschemacher H., eds.) VCH, Weinheim, 1994,, p161-169.

Heart disease and cardiovascular disease
Epidemiological (population) studies
Countries that have more A1 beta casein in their milk have a higher risk of heart disease.	beta-casein A1, ischaemic heart disease mortality, and other illnesses. McLachlan, C. N. S. 2001. Medical Hypotheses. 56(2), 262-272
Data from 20 countries show that A1 beta casein consumption increased Heart Disease rates	Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein. Laugesen M & Elliott R, 2003. New Zealand Medical Journal 116(1168) U295.
Animal feeding studies
Animals fed more A2 beta casein than A1 had fewer signs of cardiovascular damage. A2 fed animals showed no damage to arteries and reduced damage even after cholesterol intake.	A casein variant in cow’s milk is atherogenic. Tailford KA, Berry CL, Thomas AC, Campbell JH. 2003 Atherosclerosis. 170(1):13-9
Human studies
Infant formula containing cow milk beta caseins is linked to higher levels of antibodies to oxidised LDL in infants, which shows that these infants have been exposed to biofactors linked to heart disease. BCM-7 from A1 beta casein has been shown to oxidise LDL, which is strongly linked to heart disease.	Significant increase in antibodies against oxidized LDL particles (Igox LDL) in three-month old infants who received milk formulae. Steinerová A, Racek J, Rajdl D, Stoicky F, Rokyta Z, Trefil L, Korotvik a M 2004 Letter to the Editor. 173(1) pp 147-148 Autoantibodies against oxidised LDL in the first phase of life Steinerova A, Racek J, Stozicky F, Tatzber F, Lain A 1999.. Clin. Chem. Lab. Med. 37(9), pp 913-7 Antibodies against oxidised LDL in infants Steinerova A, Racek J, Stozicky F, Tatzber F, Zima T, Setina R 2001.. Clin. Chem. 47(6) pp 1137-8
Other studies
Bioactive components of milk including beta casein peptides that have positive cardiovascular effects.	Natural bioactive substances in milk and colostrum: effects on the arterial blood pressure system Groziak SM, Miller GD. (2000). Br J Nutr. 84 Suppl 1:S119-25 Bioactive substances in milk with properties decreasing risk of cardiovascular diseases Pfeuffer M, Schrezenmeir J. (2000). Br J Nutr 84 Suppl 1:S155-9. Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus CP790. Yamamoto N, Akino A, Takano T. J Dairy Sci. 1994 Apr;77(4)917-22
BCM-7 (from bovine A1 beta casein) promotes the oxidation of human low density lipoprotein (LDL) linking bovine A1 beta casein with an increased risk of Heart Disease	Casein-derived peptides can promote human LDL (low-density lipoproteins) oxidation by a peroxidase- dependent & metal-independent process. Torreilles J & Guerin MC. 1995. C R Seances Soc Biol Fil 189(5):933-42

Beta casein peptides linked to the symptoms of neurological conditions
Human studies
Milk containing A2 beta casein was found not to aggravate neurological disorders	Milk containing beta casein with proline at position 67 does not aggravate neurological disorders; PCT WO0219832; Crawford RA, Boland MJ, Norris CS, Hill JP, Fenwick RM.
Beta casomorphins found in the urine of autistic children are linked to the aggravation of the symptoms of Autistic Spectrum Disorders (ASD)	Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Reichelt KL, Knivsberg AM. (2003) Nutr Neurosci 6(1):19-28
A1 beta casein peptide BCM7 can cross the blood brain barrier and affect brain regions shown to alter in schizophrenic and autistic patients.	ß-Casomorphin Induces Fos-Like Immunoreactivity in Discrete Brain Regions Relevant to Schizophrenia and Autism Zhongjie Sun, J. Robert Cade, Melvin J. Fregly, R. Malcolm Privette. University of Florida, USA. Autism, Vol. 3, No. 1, 67-83 (1999)
A gluten and casein free diet improved most behaviours in autistics and reduced symptoms in schizophrenic patients. Reduced levels of BCM-7 (from A1 beta casein) corresponded to improvements in symptoms.	Autism and Schizophrenia: Intestinal Disorders, Cade R et al. (2000) Nutritional Neuroscience 3: 57-72.
A gluten and casein free diet resulted in a significant reduction of symptoms in autistic children linking gluten and casein consumption in the symptoms associated with autistic spectrum disorders	Reports on dietary intervention in autistic disorders Knivsber AM, Reichelt KL, Nodland M. (2001). Nutr Neurosci. 4(1):25-37 A randomised, controlled study of dietary intervention in autistic syndromes Knivsberg AM, Reichelt KL, Hoien T, Nodland M. (2002). Nutr Neurosci. 5(4):251-61

Beta casein variants
Human studies
A1 and A2 beta casein are found in Holstein cattle. A quarter of Holsteins have only A1 genes, a quarter have only A2 genes and a half have 1 A1 and 1 A2 gene.	Association between milk protein genetic variants and genetic values of Canadian Holstein bulls for milk yield traits. Sabour MP, Lin CY, Lee AJ, McAllister AJ..J Dairy Sci. 1996 Jun;79(6):1050-6. Casein polymorphism and relation between milk production traits G. Freyer, Z. Liu, G. Erhardt, L. Panicke 1999. Journal of Animal Breeding and Genetics 116 (2), 87–97.
Dairy milk contains a balance of a1 and a2 beta casein on average	Milk Protein Polymorphisms in California Dairy Cattle. 1991 J Dairy Sci 74:1730-1742 Alison van Eenennaam and Juan Fernando Medrano. Department of Animal Science. University of California. Davis 956168521
A2 beta casein is the original form of beta casein. A1 beta casein has evolved more recently.	Ng-Kwai-Hang, K.F., and F. Grosclaude. 2002. Genetic polymorphism of milk protein. Chapter 16 pp 737-814 In Advanced Dairy Chemistry: Volume 1 – Proteins, 2nd Edition (edited by P.F. Fox and P. L. H. McSweeney) Kluwer Academic/Plenum Publishers, New York http://www.mcgill.ca/animal/staff/ng/
A1 beta casein is more common in more modern cattle breeds.	Milk protein loci polymorphism in taurine (Bos taurus) and zebu (Bos indicus) populations bred in hot climate G. Ceriotti, D. Marletta, A. Caroli, G. Erhardt (2004) Journal of Animal Breeding and Genetics 121 (6), 404– 415.
A2 beta casein is the original form of beta casein from which all the other beta casein types evolved.	Milk protein polymorphism: detection and diffusion of the genetic variants in Bos genus (1999) P. Formaggioni, A. Summer, M. Malacarne, P. Mariani Università degli Studi di Parma, Annali della Facoltà di Medicina Veterinaria Vol. XIX

Bioactive digestion products of beta casein variants
BCM-7 is uniquely released from A1 variant of bovine beta casein	Enzymatic release of neocasomorphin and beta-casomorphin from bovine beta-casein Jinsmaa, Y & Yoshikawa, M. 1999.. Peptides V20(8), pp 957-962.
Comprehensive reviews of the bioactivity and physiological function of milk protein fragments including beta-casomorphins (BCMs)	Multifunctional peptides encrypted in milk proteins Meisel H. (2004). Biofactors 21(1-4):55-61 Effects of Milk-derived bioactives: an overview. Shah, N. 2000. British Journal of Nutrition. 84. Suppl. 1. S3-310. Biologically active peptides in milk proteins. Meisel H, Frister H, Schlimme E. Z Ernahrungswiss. 1989 Dec;28(4)267-268 Purification and identification of potentially bioactive peptides from enzyme-modified cheese. Haileselassie SS, Lee BH, Gibbs BF. J Dairy Sci. 1999 Aug;82(8):1612-7. Database of biologically active peptide sequences. Dziuba J, Minkiewicz P, Nalecz D, Iwaniak A. Nahrung. 1999 Jun;43(3):190-5. Review. Identification of Peptides Derived from B-casein Hydrolysates by Proteolytic Enzymes. Park, S. Y. Gibbs B. F. Lee B. H. 1996. Korean J. Dairy Sci. 18 (4):237-246. (Korean)
Peptides from Beta Casein including the BCMs have been shown to affect gut processes	Effects of caseinomacropeptide (CMP) on digestion regulation. Yvon M, Beucher S, Guilloteau P, Le Huerou-Luron I, Corring T. Reprod Nutr Dev. 1994;34(6):527-37. Review. Effect of casein and beta-casomorphins on gastrointestinal motility in rats. Daniel H, Vohwinkel M, Rehner G J Nutr. 1990 Mar;120(3):252-7. Effect of opioid active therapeutics on the ascending reflex pathway in the rat ileum. Allescher HD, Storr M, Piller C, Brantl V, Schusdziarra V 2000. Neuropeptides. 34(3-4):181-6. Effects of beta-casomorphin derivatives on gastrointestinal transit in mice. Becker, A. Hempel G, Grecksch G, Matthies H. 1990. Biomed Biochim Acta. 49(11):1203-7. Cow milk consumption in constipation and anal fissue in infants and young children Andiran F, Dayi S, Mete E. 2003.. J. Paediatr. Child. Health. 39(5):329-331. Intragastric beta-casomorphin (1-7) attenuates the suppression of fat intake by enterostatin White CL, Bray GA, York DA. 2000.. Peptides 2000 21(9):1377-81 Effects of peptides derived from dietary proteins on mucus secretion in rat jejunum Claustre J, Toumi F, Trompette A, Jourdan G, Guignard H, Chayvialle JA, Plaisancie P. 2002. Am J Physiol Gastrointest Liver Physiol Sep;283(3):G521-8. Beta-casomorphin (BCM) and human colonic lamina propria lymphocyte proliferation. Elitsur Y, Luk GD. (1991). Clin Exp Immunol. 85(3):493-7.

Beta casomorphins (BCMs)
BCM-7 is uniquely released from A1 variant of bovine beta casein	Enzymatic release of neocasomorphin and beta-casomorphin from bovine beta-casein Jinsmaa, Y & Yoshikawa, M. 1999.. Peptides V20(8), pp 957-962.
BCM-7 was found in the guts of human subjects after they drank cows milk.	Demonstration of beta-casomorphin immunoreactive materials in in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans. Svedberg J, de Haas J, Leimenstoll G, Paul F, Teschemacher H. Peptides. 1985 Sep-Oct;6(5):825-30.
BCM7 is resistant to break down.	Casomorphins reduce separation distress in chicks. Panksepp J, Normansell L, Siviy S, Rossi J 3rd, Zolovick AJ.1984 Peptides 5(4):829-31
BCMs detected in the blood and central nervous system (CNS) of humans and animals	Casein peptide release and passage to the blood in humans during digestion of milk or yogurt Chabance B, Marteau P, Rambaud JC, Migliore-Samour D, Boynard M, Perrotin P, Guillot R, Jolles P, Fiat AM 1998.. Biochimie 80(2), pp 155-165. Micropurification and amino acid sequence of beta-casomorphin-8 in milk from a woman with postpartum psychosis. Renlund S, Erlandsson I, Hellman U, Silberring J, Wernstedt C, Lindstrom L, Nyberg F. 1993. Peptides.14(6):1125-32 Demonstration of a beta-casomorphin immunoreactive material in the plasma of newborn calves after milk intake Umbach M, Teschemacher H, Praetorius K, Hirschhauser R, Bostedt H. 1985. Regul Pept. Nov 7;12(3):223- 30. beta-Casomorphin-immunoreactivity in the brain stem of the human infant. Pasi A, Mahler H, Lansel N, Bernasconi C, Messiha FS.1993 Res Commun Chem Pathol Pharmacol. 80(3):305-22.
BCMs shown to have strong opioid activity	Meisel, H & FitzGerald, RJ. 2000. Opioid peptides encrypted in intact milk protein sequences. British Journal of Nutrition, 83, Suppl. 1. S27-S31 Rotational behaviour produced by intranigral injections of bovine and human beta-casomorphins in rats Herrera-Marschitz M, Terenius L, Grehn L, Ungerstedt U.. 1989. Psychopharmacology (Berl).99(3):357-61 Relation of beta-casomorphin to Apnea in Sudden Infant Death Syndrome Sun Z, Zhang Z, Wang X, Cade R, Elmir Z, Fregly M. 2003.. Peptides 24(6):937-943. beta-Casomorphins induce apnea and irregular breathing in adult rats and newborn rabbits. Hedner J, Hedner T. 1987 Life Sci 41(20):2303-12. Delayed behavioral effects of beta-casomorphin-7 depend on age and gender of albino rat pups Dubynin VA, Malinovskaya IV, Ivleva YA, Andreeva LA, Kamenskii AA, Ashmarin, IP 2000. . Bull. Exp. Biol. Med. 130(11), pp1031-1034.
Beta casein peptides and BCMs found to affect the human immune system	Casein, a prohormone with an immunomodulating role for the newborn? Migliore-Samour D, Jolles P. Experientia. 1988 Mar 15;44(3):188-93. Review. Pseudoallergic skin reactions to opiate sequences of bovine casein in healthy children Kurek M, Czerwionka-Szaflarska M, Doroszewska G. 1995.. Rocz Akad Med Bialymst. 40(3):480-5. A naturally occurring opioid peptide from cow’s milk, beta-casomorphine-7, is a direct histamine releaser in man Kurek M, Przybilla B, Hermann K, Ring J. 1992.. Int Arch Allergy Immunol. 97(2):115-20.

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