Review

A2 Bovine Milk and Caprine Milk as a Means of Remedy for

Milk Protein Allergy
Young W. Park 1, * and George F. W. Haenlein 2

1 Georgia Small Ruminant Research & Extension Center, Fort Valley State University,
Fort Valley, GA 31030, USA
2 Department of Animal and Food Sciences, University of Delaware, Newark, DE 19717, USA;
[email protected]
* Correspondence: [email protected]; Tel.: +1-478-827-3089

Abstract: A new type of cow’s milk, called A2 milk, has appeared in the dairy aisles of supermarkets
in recent years. Cows’ milk generally contains two major types of beta-casein as A1 and A2 types,
although there are 13 genetic variants of β-casein: A1, A2, A3, A4, B, C, D, E, F, H1, H2, I and G.
Studies have shown that A1 β-casein may be harmful, and A2 β-casein is a safer choice for human
health especially in infant nutrition and health. The A2 cow milk is reportedly easier to digest
and better absorb than A1 or other types of milk. The structure of A2 cow’s milk protein is more
comparable to human breast milk, as well as milk from goats, sheep and buffalo. Digestion of A1
type milk produces a peptide called β-casomorphin-7 (BCM-7), which is implicated with adverse
gastrointestinal effects on milk consumption. In addition, bovine milk contains predominantly αs1 -
casein and low levels or even absent in αs2 -casein, whereby caprine milk has been recommended as
an ideal substitute for patients suffering from allergies against cow milk protein or other food sources.
Since goat milk contains relatively low levels of αs1 -casein or negligible its content, and αs2 -casein





 levels are high in the milk of most dairy goat breeds, it is logical to assume that children with a high
milk sensitivity to αs1 -casein should tolerate goat milk well. Cow milk protein allergy (CMPA) is
Citation: Park, Y.W.; Haenlein, G.F.W.
considered a common milk digestive and metabolic disorder or allergic disease with various levels
A2 Bovine Milk and Caprine Milk as
a Means of Remedy for Milk Protein
of prevalence from 2.5% in children during the first 3 years of life to 12–30% in infants less than
Allergy. Dairy 2021, 2, 191–201. 3 months old, and it can go up to even as high as 20% in some countries. CMPA is an IgE-mediated
https://doi.org/10.3390/ allergy where the body starts to produce IgE antibodies against certain protein (allergens) such as
dairy2020017 A1 milk and αs1 -casein in bovine milk. Studies have shown that ingestion of β-casein A1 milk can
cause ischemic heart disease, type-1 diabetes, arteriosclerosis, sudden infant death syndrome, autism,
Academic Editor: Michele Faccia schizophrenia, etc. The knowledge of bovine A2 milk and caprine αs2 -casein has been utilized to
rescue CMPA patients and other potential disease problems. This knowledge has been genetically
Received: 10 September 2020 applied to milk production in cows or goats or even whole herds of the two species. This practice has
Accepted: 17 March 2021
happened in California and Ohio, as well as in New Zealand, where this A2 cow milk has been now
Published: 6 April 2021
advanced commercially. In the USA, there have been even promotions of bulls, whose daughters
have been tested homozygous for the A2 β-casein protein.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
Keywords: bovine milk; caprine milk; cow milk protein allergy; αs1 -casein; αs2 -casein; A1 β-casein
published maps and institutional affil-
milk; A2 β-casein milk; genetic polymorphism; therapeutic value
iations.

1. Introduction
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
Bovine milk allergy caused by protein genetic variants has been regarded as a common
This article is an open access article
milk digestive and allergic disease [1] with various levels of prevalence from 2.5% in
distributed under the terms and children during the first 3 years of life [2] to 12–30% in infants less than 3 months old [3]
conditions of the Creative Commons and an overall frequency in Scandinavia of 7–8% [4]. However, it can go up to even as high
Attribution (CC BY) license (https:// as 20% in some countries [3].
creativecommons.org/licenses/by/ Milk proteins basically consist of 80% casein and 20% whey proteins. Bovine and
4.0/). caprine milk contain four types of caseins, which are αs1 -casein, αs2 -casein, β-casein and

Dairy 2021, 2, 191–201. https://doi.org/10.3390/dairy2020017 https://www.mdpi.com/journal/dairy

Dairy 2021, 2 192

k-casein [5]. Some infants and adult patients are implicated with cow milk protein allergy
(CMPA), lactose intolerance, other digestive problems and eczema, etc., due to the existence
of allergenic proteins in the milk. Among the four types of caseins, the unique protein
fractions of β-casein have drawn a special interest and attention to scientists and dairy
consumers due to a potential relationship exists between β-casein genotype of the bovine
milk protein and the health of cow’s milk consumers. β-casein has been shown to exist
as A1 and A2 forms, where the A1 milk contains A1 β-casein, and A2 milk contains A2 β-
casein, respectively. The two allele forms of A1 and A2 milk are determined by the existence
of two different amino acids, which are histidine or proline in the β-casein molecule [5–7].
During human digestion, the beta-casomorphin-7 (BCM-7) is generated from A1
bovine milk proteins, which has shown to be the primary causative factor for health and
digestive disorders associated with A1 milk. On the other hand, no relationship has been
found between the presence of A2 β-casein in the milk and cow milk protein allergy
(CMPA) or health problems [8]. Many studies have shown that BCM-7 generated from A1
bovine milk causes human health hazards, since it has been shown to have potentials in
influencing a variety of opioid receptors in the endocrine, nervous and immune system,
including diabetes, heart diseases, schizophrenia, autism, etc. [7–14].
In terms of αS casein composition, caprine milk generally has higher αs2 -casein
content than bovine milk does, although there are differences in levels of αs1 - and αs2 -
casein between different breeds within each species. Goat milk has significantly lower
αs1 - and higher αs2 -casein concentrations than cow milk contains. Caprine milk has been
shown to be hypoallergenic for ordinary consumers and CMPA patients due to the higher
αs2 -casein content in its milk [15,16]. However, when it comes to goat cheese making,
dairy farmers and cheese manufacturers would prefer to have αs1 -casein milk due to
the production of firmer curds and higher cheese yield in contrast to the milk having
higher αs2 -casein. On the other hand, milk having higher αs2 -casein produces a softer curd
and a lower cheese yield, but it gives higher digestibility, which is beneficial in human
nutrition [3,16]. In contrast, milk containing high αs1 -casein has been reportedly linked
to higher incidences of milk allergy and digestive problems in certain infants and CMPA
patients [3,15,16]. Thus, the purpose of this article is to review and reiterate the recent
knowledge and research progresses in A2 cow milk as well as goat milk with respect to
remedy milk protein allergy and human wellbeing.

2. Beta-Casein Genetic Variants and Polymorphism

Among milk proteins, the concentration of β-casein is the second highest among all
proteins in cow milk (Table 1) [5]. With respect to αs1 - and αs2 -casein compositions in
bovine milk, it contains 38% αs1 - and 12% αs2 -casein, where αs1 -casein has been reportedly
associated with cow milk allergy [13,15–17]. In contrast, β-casein content of goat milk is the
highest (54.8%) among all its caseins (Table 1) [7], and caprine milk contains significantly
higher αs2 -casein than bovine milk. Many previous reports have shown that this unique
compositional characteristic of caprine milk is highly correlated with the therapeutic and
hypoallergenic properties of its milk in infants and especially in CMPA patients [14,17–19].
Amalfitano et al. (2020) [1] reported that in terms of percentage of milk N, the genotypes
of CSN3 notably affected all the casein fractions, whereas the BLG genotypes had a much
greater influence on most non-casein traits. The genotypes of the CSN2 gene exerted an
appreciable effect on αS2 -CN and not β-CN. For an amount (g/L) of β-CN, the effect of
breed was revealed to be significant (12%), whereas breed was almost insignificant before
the inclusion of genotypes.
Since the potential relationship has been shown between A2 milk consumption and
the health of milk consumers, it is essential to understand the genetic variants of β-casein
and their biochemical and physiological functionalities. Thirteen β-casein genetic variants
have been identified, including A1, A2, B, C, D, E, F, H1, H2, I and G (Table 2), which have
been reviewed by several authors [14,20,21]. Givens et al. (2013) [22] showed that β-casein
in UK retail milk comprises approximately 0.58, 0.31, 0.07 and 0.03 A2, A1, B and C protein
Dairy 2021, 2 193

variants, respectively. The A4 allele was found in Korean native cattle, while the nucleotide
substitution has not been recognized yet. Among the β-casein genetic variants, the most
common forms of β-casein in dairy cow breeds are A1 and A2, whereas B variant is less
common, and A3 and C alleles are rare [23]. The difference between A1 and A2 bovine
milk is that there is an amino acid substitution at the 67th position of the protein chain,
where proline of A2 variant is substituted by histidine of variant A1 [24,25], meaning that
A1 milk has histidine, while A2 milk has proline in position 67 of the β-casein.

Table 1. Comparison of protein composition among cow, goat and human milks.

Proteins Cow Goat Human

Protein (%) 3.3 3.5 1.2
Total casein (g/100 mL) 2.70 2.11 0.40
αs1 (% of total casein) 38.0 5.6 —
αs2 (% of total casein) 12.0 19.2 —
β (% of total casein) 36.0 54.8 60–70.0
κ (% of total casein) 14.0 20.4 7.0
Whey protein (%) (albumin and globulin) 0.6 0.6 0.7
Data adapted from [5].

Table 2. Changes in the amino acid sequence of beta-casein variants.

Beta-Casein Changes in Amino Acid Sequence

Variants 18 25 35 36 37 67 72 88 93 106 117 122 137 138
A2 Ser-P Arg Ser-P Glu Glu Pro Glu Leu Gln His Gln Ser Leu Pro
A1 His
A3 Gln

B His Arg
C Ser Lys His
D Lys
E Lys
F His Leu
G His Leu
H1 Cys Ile
H2 Glu Leu Glu
I Leu
Data adapted from [15].

On the other hand, A2 milk prevents the breakdown at the amino acid chain at position
67 due to proline and generates another peptide called BCM-9 [26,27]. These two variants
of β-casein carried by dairy cattle are the most common and popular dairy cow breeds in
worldwide basis. In addition to A1 variant of β-casein, there are several other β-casein
variants that have the same proline substitutions at the 67th position of the amino acid chain
like A1 β-casein does, which are B, C, F and G variants of β-casein (Table 2). Using two
methods—high-resolution melting (HRM) and rhAmp® SNP genotyping—Giglioti et al.
(2020) [28] found that the limits of detection for A1 in A2 samples were 10% (100 copies) and
2% (10 copies) for HRM and rhAmp, respectively. Although both techniques were specific
in differentiating between A1 and A2 alleles, they recommended rhAmp genotyping testing
over HRM because of its enhanced sensitivity for A1.
The northern European breeds of dairy cow including Holstein, Friesian, Ayrshire and
British Shorthorn generally produce milk containing high A1 β-casein. On the other hand,
dairy cow breeds from the Channel Islands and southern France, such as Guernsey, Jersey,
Simmental, Charolais and Limousin cows, produce A2 β-casein milk [13,14].
Priyadarshini et al. (2018) [7] reported that the milk of Indian crossbred and European
breeds cattle contain the A1 protein variant, while those of the indigenous cows and buf-
Dairy 2021, 2 194

faloes in India and other Asian countries mostly have the A2 protein variant. The molecular
mass of casein is approximately 18–25 kDa. As casein molecule is developed through
posttranslational modifications and alternative splicing of the gene product and genetic
polymorphisms, it is quite heterogeneous in nature [9,12,13].

3. Formation of BCM-7, Its Bioactivity and Quantification

Beta-casomorphins (BCMs) are peptide chains containing 4–11 amino acids (aa), de-
rived from β-casein molecules. All these BMC peptides begin with tyrosine amino acid
residue in position 60 [27]. Upon digestion, A1 β-casein milk releases BCM-7, which is a
bioactive peptide 7 amino acid (Tyr-Pro-Phe-Pro-Gly-Pro-Ile), which possess morphine-like
activity [29]. This BCM-7 exhibits several bioactivities such as a strong opioid activity [30],
stimulating human lymphocyte T proliferation in vitro [31] and cytomodulatory proper-
ties [32].
The sequence of BCM-7 is located at positions 60–66 of the bovine beta-casein AA
chain [14]. The BCM-7 is generated with digestive actions of pepsin, pancreatic elastase
and leucine aminopeptidase by in vitro gastrointestinal digestion of β-casein A1 and B
(but not A2) [33–35]. The peptide bond between Ile and His is cleaved by elastase, which
releases the carboxyl terminus of BCM-7 [14]. The amino terminal of this peptide can be
released by the required enzymes of pepsin and leucine aminopeptidase (Figure 1) [34].
Nguyen et al. (2021) [35] observed that β-CM7 was not released after gastrointestinal
digestion of heated A2A2 milk, and β-CM7 was released after gastrointestinal digestion
of heated A1A1 and A2I milk. This difference occurred by the mutation accounts for the
polymorphism of a single nucleotide at codon 67 of the β-casein gene: CCT (A2, proline)
CAT (A1, histidine) [36]. A conformational difference in the expressed protein by the
secondary structure may be attributable to the difference in AA sequence. Hydrolyzed
variant A1 β-casein of bovine milk contained four times higher content of BCM-7 than in A2
milk [14]. Traces of BCM-7 were found in fresh milk due to the absence of proteolysis [37].
Nevertheless, precursors of BCMs were observed in Cheddar, Swiss, Limburger, Blue and
Brie cheeses, while BCMs were not existed due to the possible degradation by enzymatic
proteolysis caused by the starter culture or the possible presence of undetectable amounts
Dairy 2021, 2, x FOR PEER REVIEW    5  of  11 
  of these peptides [38]. Large quantities of BCM-like and morphiceptin-like activities in
infant formulas were also identified [38].

 
Figure 1. Release of beta-casomorphin-7 from beta-casein variant A1 but not from A2 (adapted from [14,34]). 
Figure 1. Release of beta‐casomorphin‐7 from beta‐casein variant A1 but not from A2 (adapted from [14,36]).

Table 3. In vitro gastrointestinal digestion of β‐casein variants using pepsin and pancreatic enzymes 1. 

β‐CN  tpep  tpan  DH 

MLP 5 
Variant  (min) 2  (min) 3  (%) 4 
Dairy 2021, 2 195

Using liquid chromatography coupled with electrospray ionization mass spectrometry

(LC/ESI-MS), Petrat-Melin et al. (2015) [22] confirmed the identity and purity of the isolated
β-CN variants. The β-CN is assumed to be 40% of total CN, whereby the amount of β-CN
was calculated by the purification process. With milk composition data of Milkoscan
combined with protein quantification by AA analysis, the yields of the four isolated β-CN
variants, A1, A2, B and I, were estimated, which were between 5 and 20% of total β-CN
originally present in the milk samples, and the purity relative to total protein determined
by LC/ESI-MS varied from 89.2 to 93.2% [22]. After 60 min of pepsin digestion, the degree
of hydrolysis (DH) for the β-CN variants showed approximately 3% with an enzyme:
substrate ratio of 1:200 in the reaction (Table 3). The DH increased to around 20% after
5 min digestion with pancreatic enzymes, and DH became close to 50% after 120 min for
all β-CN variants, in the order of DH being A 1 > A 2 > I > B. The authors indicated that
DH could be converted to a mean length of peptides by 100%/DH as shown in Table 3.

Table 3. In vitro gastrointestinal digestion of β-casein variants using pepsin and pancreatic enzymes 1 .

β-CN tpep tpan DH

MLP 5
Variant (min) 2 (min) 3 (%) 4
A1 60 0 3.6 ± 0.42 a 27.6 ± 3.01
A2 60 0 3.2 ± 0.20 a 31.5 ± 2.20
B 60 0 3.6 ± 0.22 a 28.0 ± 1.95
I 60 0 2.6 ± 0.17 a 37.6 ± 2.46
A1 60 5 20.4 ± 1.71 b 4.9 ± 0.42
A2 60 5 21.5 ± 2.47 b 4.6 ± 0.55
B 60 5 20.2 ± 0.89 b 5.0 ± 0.20
I 60 5 19.4 ± 1.38 b 5.2 ± 0.33
A1 60 120 55.0 ± 5.99 c 1.8 ± 0.21
A2 60 120 52.4 ± 5.54 c 1.9 ± 0.19
B 60 120 46.2 ± 3.98 c 2.2 ± 0.16
I 60 120 49.9 ± 4.24 c 2.0 ± 0.17
a–cDifferent letters denotes significant difference (p < 0.001). 1 Results are shown as the mean ± SEM (n = 3;
n = 2 for A 1 ). 2 tpep = reaction time with pepsin. 3 tpan = reaction time with pancreatic enzymes. 4 DH = degree of
hydrolysis. 5 MLP (100%/DH) = mean length of peptides. Adapted from Petrat-Melin et al. [22].

4. β-Casein A1 Milk Allergy and Its Symptoms

Gastrointestinal digestion or hydrolysis of bovine milk proteins in vitro or in vivo
has shown to generate the bioactive peptide beta-casomorphin 7 (BCM-7) from β-casein
variants A1 and B, whereas the peptide is not produced from variant A2 milk. It has
been reported that the BCM-7 level is four-fold higher in variant A1 of β-casein digested
proteolyzed milk than the BCM-7 level of A2 milk ([15,39]. Many dairy cow breeds
commonly have variants A1 and A2 of β-casein [40].
Epidemiological evidence has revealed that consumption of A1 β-casein is correlated
with human disease, indicating that BCM-7 from A1 bovine milk can be a risk factor for
type 1 diabetes, human ischemic heart disease (IHD), atherosclerosis and sudden infant
death syndrome [8–11,38]. The World Health Organization (WHO) suggested the risk factor
data for several diseases and mortality data attributed to BCM-7 from A1 bovine milk. The
populations consuming high levels of β-casein A2 in the milk appeared to have a lower
occurrence of type 1 diabetes [41], cardiovascular disease and a possible sudden infant
death syndrome [12–14]. Furthermore, a higher level of BCM-7 consumption is associated
with neurological disorders, such as autism and schizophrenia. Deeper researches on
protein polymorphism are necessary to verify the range and nature of BCM-7 interactions
with the human gastrointestinal tract and whole organism.
A high intake of A1 β-casein is shown to be a risk factor for IHD [10], and the
association was shown between IHD rate and β-casein A1 consumption in males of
30–69 old for 16 countries (Australia, France, Iceland, Austria, Canada, Denmark, Finland,
Norway, Scotland, Sweden, Israel, Japan, New Zealand, West Germany, United Kingdom
Dairy 2021, 2 196

and USA) [10]. In addition, A1 β-casein consumption was found to cause atherosclerosis
or hypercholesterolemia in many species’ animal research such as pigs, rabbits, rodents
and monkeys [10,39]. In a multi-center, randomized controlled study, effects of cow’s milk
β-casein variants on symptoms of milk intolerance were observed in Chinese adults [42].
The physiological effect of BCM-7 in A1 β-casein may have an influence on the oxidation
and/or peroxidation of a lipid component of low-density lipoprotein (LDL) [40].
A significant association was also found epidemiologically between the intake of
A1 milk and the incidence of diabetes mellitus type 1 (DM-1) [10,11,39], which was not
observed in A2 milk consumption. In an evaluation of the annual cow milk protein con-
sumption and DM-1 cases in children of 0–14 year old in 10 countries, it was observed that
the intake of total protein was not correlated with the incidence of DM-1 (r = 0.402), whereas
consumption of the β-casein A1 variant showed a high correlation (r = 0.726) [43]. Further-
more, the correlation between the consumption of β-casein A1 + B and the occurrence of
DM-1 was even higher (r = 0.982). The A1 β-casein consumption across 16 countries was
associated strongly (r = 0.75) with the occurrence of DM-1. The BCM-7 released by β-casein
reportedly inhibit the proliferation of in vitro human intestinal lymphocyte. This type
of immune suppressant may influence the development of intestinal immune tolerance
and may suppress defense mechanisms towards enteroviruses, where both cases may be
implicated in the etiology of DM-1 [11,43]. On the other hand, Thakur et al. (2020) [44]
found that feeding A1 or A2 cow-milk-derived casein hydrolysates did not cause any
deteriorative effect on the blood biochemical profile and histopathology of major organs
such as heart, liver and kidney.
Milk is one common factor to develop the sudden infant death syndrome (SIDS) in all
children [8], which causes the death of infants during the first year of the life, beginning
at the end of the first month [40]. After BCMs are absorbed from the gastrointestinal
tract, these compounds can cross over the blood–brain barrier because of the immaturely
developed central nervous system in infants. Depression of the brain-stem respiratory
centers can occur in infants due to the ingestion of the opioid peptides like BCM-7, which is
derived from A1 milk. This condition can lead to infant death due to abnormal respiratory
control and vagal nerve development [14]. The BCM immunoreactivity was found in
the brain stem of the human infant. BCM-7 can be absorbed by infants due to immature
gastrointestinal tract [44], where significant elevations of BCM-7 levels in infant patient’s
blood [42,43] and in urine showing autism, schizophrenia and postpartum psychosis [45].
CMPA sometimes can be confused with lactose intolerance (LI), where LI is not
associated with the immune system of the body. CMPA and LI share some signs and
symptoms, including stomach and gut problems such as wind and diarrhea, while CMPA
usually occurs in babies younger than 1 year old, LI is very rare in children under 5 years
of age [46]. CMPA is a type of milk allergy of a baby’s immune responses to bovine
milk protein, causing allergic symptoms such as digestive system (diarrhea, vomiting,
constipation and reflux), respiratory system (noisy breathing, coughing, runny nose) and
the skin (rash, hives, dry, scaly or itchy skin) [46].

5. A2 Milk and Goat Milk as a Remedy of CMPA

Many studies have reported that consumption of A1 β-casein bovine milk caused
CMPA, including increased gastrointestinal inflammation, elevated digestive discomfort
after milk ingestion, delayed transit, which are metabolically linked to type 1 diabetes,
cardiovascular disease, atherosclerosis and decreased cognitive processing speed and accu-
racy [19–21]. Since these digestive discomforts and some symptoms of lactose intolerance
may stem from the ingestion of A1 β-casein milk, the adversary gastrointestinal problems
of A1 β-casein milk can be alleviated and resolved by consumption of only A2 β-casein
milk. The A2 cow milk, therefore, has emerged and recommended for remedy of CMPA.
There are differences in protein structures and amino acids makeup in milk compo-
sition within and between dairy species, such as cow and goats. There are two variants
of αS-casein—αs1 - and αs2 -casein—where αs1 -casein is linked to cow milk allergy. Since
Dairy 2021, 2 197

cow milk contains αs1 -casein as its dominant protein, goat milk has been recommended
often as a cure for cow milk allergy [15,16]. The dominant protein in goat milk is αs2 -casein,
not αs1 -casein, which makes goat milk less allergenic. The differences in amino acid com-
position between αs1 - and αs2 -casein in bovine and caprine milk may be accountable for
the allergenicity of cow milk with αs1 -casein in contrast to the hypoallergenicity of goat
milk with αs2 -casein [32]. On the other hand, the advantage of αs1 -casein is that it can form
firmer curds so that it increases cheese yield, which would be related to the economics of
dairy goat farming, not for the remedy of CMPA.
Much literature has shown that goat milk has been used for hypoallergenic and thera-
peutic foods in infants and patients who suffer from CMPA. Compared to cow or human
milk, caprine milk reportedly possesses great advantages, including high digestibility,
distinct alkalinity, high buffering capacity and certain therapeutic values in medicine
and human nutrition [17–19]. Major clinical symptomology of CMPA patients to bovine
milk proteins include rhinitis, diarrhea, vomiting, asthma, anaphylaxis, urticaria, eczema,
chronic catarrh, migraine, colitis stomach ulcer, hayfever, epigastric distress and abdominal
pain, etc. [15–17,47–52]). Over 20 years French clinical studies with CMPA patients, Sabbah
et al. (1997) [53] concluded that substitution with goat milk was followed by “undeniable”
improvements in healing CMPA symptoms. Children who are allergic to cow milk were
extensively studied in other clinical trials in France, where the results revealed that 93%
of the children treated with goat milk had positive results against CMPA. The researchers
recommended goat milk as a valuable therapeutic alternative in child nutrition because of
its reduced allergenicity and better digestibility than cow milk [54–56]. Therefore, it has
been shown that caprine milk has great therapeutic remedy functions for CMPA patients,
in addition to the efficacy of A2 bovine milk for the same cow milk allergy.

6. Commercialization of β-CN Polymorphism

Due to the health benefits of A2 β-casein containing milk, there is now an actual
dairy cow herd existing in California, which can produce milk with only A2 β-casein.
Production of this type of milk may take advantage in the market place to help people with
health concerns to drink more of their recommended three glasses of milk per day [57,58].
Likewise, a creamery in Ohio is now distributing A2 milk in 2 L cartons in Farmers Markets
of West Virginia and stores in the Washington D.C. area. Additionally, A2 milk is now on the
store dairy shelves of the Kroger Store in Barboursville, West Virginia at about USD 4.20 per
half gallon, which is twice the price of regular store milk. Active sales of A2 milk have
also been reported from Charlotte, North Carolina. Most encouraging is trade magazine
advertisement of Holstein bulls with the A2/A2 beta casein genetics such as for “Dun-
Did Bush Wacker”-ET A2/A2 by Triple-Hil Sires, EX-90 3 yr/aAa: 354/62/Smithsburg,
Maryland in the leading Pennsylvania dairy magazine Farmshine in their 24 January 2020
issue [59]. A feature article in the North American edition of the International Holstein
Hub magazine discusses the A2 phenomenon in length [60] and stated “While the health
benefits of A2 milk may not be entirely certain, it is clear that a niche market has been
created that commands a price premium. With a growing supply of A2A2 bulls to select
from, breeding cows to fill that niche becomes an attractive proposition. Indeed, with
the A2A2 bulls ranking as high as the Nr. 3 on the TPI charts, then breeding for A2 does
not require a lot of compromise in other areas”. Thus, there maybe now the beginning of
“taylor-made”, the A2 milk, coming to the rescue of consumers.
In order to test dairy cows and market milk containing only the A2 variant of β-casein,
New Zealand established a company called the “A2 Corporation Ltd.” in 2000. A DNA test
kit has been developed by this corporation, where the test kit can determine if the animal
belongs to A1 or A2 or a combination of both, by analyzing a hair plucked from a cow’s
tail [14]. The selective distribution of bull semen is the easiest way to use the desirable
β-casein A2 genotypes. The herds of dairy cattle producing milk with A2 variant only can
be developed by this method. As a premium brand of cow milk, this specific A2 variant of
β-casein milk has been commercially marketed in New Zealand and Australia since 2003,
Dairy 2021, 2 198

where this offers the consumers a natural choice of A2 milk. The same corporation has also
launched marketing this healthy and therapeutically advantageous A2 milk in Asia and
the United States [14].

7. Conclusions
Finding hypoallergenic and nutritionally healthy foods is greatly important for the
wellbeing of people who have allergies against bovine milk and other foods. Certain
percentage of infants (8–20%) and adult patients suffer from cow milk allergy, lactose
intolerance, other digestive problems and skin allergies, due to the existence of allergenic
proteins in the milk. Although there are 13 genetic variants of β-casein in bovine milk, it
contains two major types of beta-casein as A1 and A2 types. Studies have shown that A1
β-casein is harmful and A2 β-casein is a safer choice for human health especially in infant
nutrition and health. The A1 type β-casein in bovine milk releases β-casomorphin-7 (BCM-
7) peptide by proteolytic digestion, where BCM-7 is implicated in adverse gastrointestinal
problems of milk consumption. Milk that contains A1 β-casein and A2 β-casein are known
as A1 milk and A2 milk, respectively. The A1 variant β-casein is produced in the milk of
crossbred with European cow, mainly Black and White Holstein-Friesians, while Guernseys
are mostly A2, and Jerseys, Ayrshires and Brown Swiss are mixed. Because A1 β-casein
milk causes allergic reactions, A2 bovine milk has emerged as the healthy milk to rescue
people who have allergies and digestive disorders with cow milk consumption.
A1 β-CN contains a histidine residue rather than proline at the amino acid position
67, which allows to release the seven amino acid residues, BCM-7. This released peptide
residue, BCM-7, from A1 β-CN milk is the major causative factor for CMPA of bovine milk.
The symptoms of milk allergy of A1 β-CN milk resembles those of lactose intolerance,
where the two types of milk allergies have different mechanisms. The BCM-7 inhibits
human intestinal lymphocyte proliferation, causing the development of a gut-associated
immune tolerance allergic effect, whereas lactose intolerance is due to the inability of
lactose digestion because of the absence of the digestive enzyme lactase. The consumption
of cow milk containing A1 β-CN can lead to the production and exposure of tissue to
BCM-7, which exerts a range of proinflammatory effects including altered epigenetic
regulation of gene expression, altered signaling activity and redox disorders, which results
in disruption of digestive process. Thus, the gastrointestinal disorders associated with
BCM-7 may be alleviated or prevented by the consumption of bovine milk containing A2
β-CN. In addition, goat milk containing a negligible amount of αs1 -casein and a high level
of αs2 -casein has shown to be hypoallergenic to CMPA patients, whereas cow milk contains
significantly high levels of αs1 -casein in and low levels of αs2 -casein. Therefore, A2 β-CN
bovine milk as well as the natural goat milk with low levels of αs1 -casein are safer choices
for human health as a means of remedy for milk protein allergy.

Author Contributions: This is a review article; writing—original draft preparation, Y.W.P. and
G.F.W.H.; writing—review and editing, Y.W.P. and G.F.W.H.; visualization, Y.W.P. and G.F.W.H.;
project administration, Y.W.P.; funding acquisition, Y.W.P. All authors have read and agreed to the
published version of the manuscript.
Funding: This publication was funded by USDA/NIFA grant number GEOX-3225.
Institutional Review Board Statement: This review article is not required for the institutional
review process.
Informed Consent Statement: Not available.
Data Availability Statement: No new data were created or analyzed in this study.
Conflicts of Interest: The authors do not have any conflict of interest.
Dairy 2021, 2 199

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