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Introduction - A2 Basics

“Since time immemorial milk has been considered as perfect food because it is an important source of nutrients and micronutrients. Milk consists of about 87 percent water and 13 percent of milk solids constituting fat, lactose, minerals and protein. Casein is the chief component of the milk proteins of which about 30-35 percent is beta-casein. Beta- casein may be of different types based on genetic background of the animals but the major types are A1 and A2. Beta-casein consist a chain of 229 amino acids. Milk having proline at 67th position of beta- casein amino acid chain is regarded as A2 milk and with histidine amino acid at this position is A1 milk. Cows producing A2 milk are known as A2 cows while those producing A1 milk are called A1 cows.”

Ref. Rajalaxmi Behera; Vol 8(4), 1-7 A1 versus A2 Milk: Impact on Human Health

Genetics behind A1 and A2 Milk

“Production of A1 or A2 milk by cows is governed by beta casein gene which is located on chromosome number 6. Since long back, cows have been producing A2 milk which is regarded as safe and nutritious. Around five thousand years back beta-casein gene was mutated and 67th amino acid was changed from proline (A2 allele) to histidine (A1 allele). A cow carries only two copies of the beta-casein gene. Hence, possibly she can be of A2A2 homozygous genotype or A1A2 heterozygous genotype or A1A1 homozygous genotype. The alleles do not have dominant - recessive relationship i.e., both the alleles are co-dominant in nature. Thus, an A1A2 cow will produce both A1 and A2 beta casein alleles in equal proportion. An A2A2 genotype cow will only produce A2 beta-casein and an A1A1 cow will only produce A1 beta-casein. A cow of A2A2 genotype will transmit the A2 allele to her progeny while an A1A1 cow will pass on the A1 allele and for A1A2 cow there is an equal chance of transmitting either allele.”

Ref. Rajalaxmi Behera; Vol 8(4), 1-7 A1 versus A2 Milk: Impact on Human Health

The Devil in A1 Milk – BCM-7

“Digestive enzymes act differently upon A1 and A2 beta-casein proteins during digestion process. Betacasomorphin-7 (BCM-7) is a bioactive seven-amino peptide is released by digestive enzymes from the A1-beta-casein protein but these enzymes cannot split the A2 protein due to presence of proline at that location. So BCM-7 is not released from A2 proteins digestion. BCM-7 interacts with the human gastrointestinal tract, internal organs, and brainstem and is regarded as the “devil” in A1 milk.”

Ref. Rajalaxmi Behera; Vol 8(4), 1-7 A1 versus A2 Milk: Impact on Human Health

“BCM7 is suggested to be associated as a risk factor for human health hazards as it can potentially affect numerous opioid receptors in the nervous, endocrine and immune system. It is also known to be an oxidant of low dietary lipoproteins (LDL) and oxidation of LDL is believed to be important in formation of arterial plaque. Epidemiological evidences claim that consumption of beta-casein A1 milk is associated as a risk factor for type-1 diabetes, coronary heart disease, arteriosclerosis, sudden infant death syndrome, autism, schizophrenia etc. A broad range of studies from American and European investigations has shown reduction in autistic and schizophrenic symptoms with decrease in A1 milk intake. Further, animal trials have also supported the linking of type-1 diabetes to milk exposure in general and A1 beta-casein in particular.”

Ref: Monika Sodhi; Indian J Endocrinol Metab. 2012 Sep-Oct; 16(5): 856. Milk proteins and human health: A1/A2 milk hypothesis

“Populations, which consume milk containing high levels of β-casein A2 variant, have a lower incidence of cardiovascular disease and type-1 diabetes. The A1/A2 hypothesis is both intriguing and potentially very important for public health if it is proved correct. It should be taken seriously and deeper research is needed to verify the range and nature of BCM7 interactions with the human gastrointestinal tract and whole organism. This requires more of animal trials and generation of data on human subjects having the problems related to A1/A2 beta-casein milk consumption.”

Ref: Monika Sodhi; Indian J Endocrinol Metab. 2012 Sep-Oct; 16(5): 856. Milk proteins and human health: A1/A2 milk hypothesis

References
Monika Sodhi; Indian J Endocrinol Metab. 2012 Sep-Oct; 16(5): 856. Milk proteins and human health: A1/A2 milk hypothesis

Rajalaxmi Behera; Vol 8(4), 1-7 A1 versus A2 Milk: Impact on Human Health

Laugesen M, Elliott R. Ischaemic heart disease, type 1 diabetes, and cow milk A1 beta-casein. N Z Med J. 2003;116:U295.

Tailford KA, Berry CL, Thomas AC, Campbell JH. A casein variant in cow's milk is atherogenic. Atherosclerosis. 2003;170:13–19.
Cade R, Privette M, Fregly M, Rowland N, Sun Z, Zele V, et al. Autism and schizophrenia: Intestinal disorders. Nutr Neurosci. 2000;3:57–72.

Diabetic Findings

A1 beta-casein milk protein and other environmental pre-disposing factors for type 1 diabetes
This study presents epidemiological, animal-based, in vitro and theoretical evidence for A1 β-casein and its β-casomorphin-7 derivative as dominant causal triggers of type 1 diabetes.

Ref; https://pubmed.ncbi.nlm.nih.gov/28504710/

Dietary Cows' Milk Protein A1 Beta-Casein Increases the Incidence of T1D in NOD Mice
This study proposes that A1 beta-casein influences T1D incidence through a number of potential mechanisms mediated via BCM-7. We hypothesise that BCM-7 released from A1 beta-casein may influence the immune response [38], gut architecture and microbiota and/or impart direct islet toxicity. Together, these effects may induce epigenetic alterations predisposing pancreatic beta-cells to an autoimmune response.

Ref; https://pubmed.ncbi.nlm.nih.gov/30213104/

Neurological Findings

Differential neurogenic effects of casein-derived opioid peptides on neuronal stem cells: implications for redox-based epigenetic changes
The results of this study reveal that the neurogenesis of NSCs is promoted by hBCM7 to a greater extent than by other opioid peptides. In fact, bBCM7 promotes higher astrocyte differentiation. The effect of hBCM7 was prominent when administered for 1 day starting on 3 dpp. The neurogenic changes regulated by bBCM7 and morphine were associated with an increase in the GSH/GSSG ratio, a decrease in the SAM/SAH ratio and a decrease in CpG methylation. These results suggest that opioid peptides derived from β-casein can influence neurogenesis via redox-based epigenetic effects. Especially peptides like bBCM7 can skew the neurogenic potential of NSC.

https://www.sciencedirect.com/science/article/pii/S0955286315003058#bb0020

Association between bovine casein antibody and new onset schizophrenia among US military personnel
This study identifies that increasing casein IgG antibody levels among those with a high initial level, drawn before diagnosis, was associated with an 18% increase in the hazard risk of schizophrenia per unit increase (value of low-positive standard) in IgG antibody levels (HR = 1.18; 95% CI 1.04, 1.34).

https://www.sciencedirect.com/science/article/abs/pii/S0920996411000855

Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia
Findings in this study suggest an immunological specificity that differs in early vs later stages of neuropsychiatric diseases and an IgG saturation by casein-derived peptides that may in part explain the reduced IgG binding to small linear epitopes observed in these patients.

https://pubmed.ncbi.nlm.nih.gov/21211944/

Gastrointestinal Findings

Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study
Our pilot study demonstrated that consuming the A1 beta-casein milk led to significantly higher BSS stool consistency values compared with the A2 beta-casein milk among a normal milk-drinking population. This finding may be linked to the known digestive release of BCM-7 from milk containing A1 beta-casein. FC values correlated highly with subjective measures of digestive discomfort on the A1 diet but less so on the A2 diet. We also showed for the A1 diet that greater abdominal pain is associated with softer stool. Furthermore, some individuals may be susceptible to A1 beta-casein as evidenced by higher FC values and associated intolerance measures.

https://www.nature.com/articles/ejcn2014127#:~:text=At%20present%2C%20there%20is%20debate,of%20beta%2Dcasomorphin%2D7.

A Comprehensive Evaluation of the Impact of Bovine Milk Containing Different Beta-Casein Profiles on Gut Health of Ageing Mice
In conclusion, the supplementation with bovine milk seems to partially counteract the ageing effect on the gut health, in particular at the proximal level. Thus, the consumption of the A2A2 milk type may be suggested as a suitable strategy to achieve positive gut health outcomes in the ageing population.

https://www.mdpi.com/2072-6643/12/7/2147

Cardiovascular Findings

Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein
Cow A1 ß-casein per capita supply in milk and cream (A1/capita) wassignificantly and positively correlated with IHD in 20 affluent countries five yearslater over a 20-year period – providing an alternative hypothesis to explain the highIHD mortality rates in northern compared to southern Europe

https://www.researchgate.net/publication/10888067_Ischaemic_heart_disease_Type_1_diabetes_and_cow_milk_A1_beta-casein