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American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
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04
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OCLC
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1121105677
Publisher:
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Servi
ABSTRACT
Relevance: Understanding of the molecular and genetic mechanisms underlying acne and acne scar formation is still
in its infancy. However, ongoing research in this area increases our knowledge of disease mechanisms and may
contribute to the development of new preventive and treatment strategies. Research confirms the significant role of
genetic factors in the development of acne, affecting its occurrence, course and effectiveness of treatment. Particular
attention is paid to gene polymorphisms associated with inflammation, androgen metabolism and the immune
response, such as CYP17A1 and TNF-
α. These data highlight the importance of taking
patients' genetic profile into
account when diagnosing and choosing therapy, which can improve treatment outcomes and prevent disease relapse.
Based on an analysis of literature data, in Uzbekistan there is insufficient understanding of the prognostic significance
and role of the NLR and TLR2 genes in the development of acne. This highlights the complexity of the genetic
component of acne and indicates the need for additional research to better understand the influence of these and
other genetic factors on the pathogenesis of the disease.
Conclusion. An in-depth study of the genetic aspects of acne will not only enrich the scientific understanding of the
disease, but will also open up new opportunities for its more effective treatment and prevention.
KEYWORDS
Acne, molecular genetic mechanisms, kelliod, prognosis.
Research Article
THE ROLE OF GENETIC MUTATIONS IN THE DEVELOPMENT OF ACNE
Submission Date:
July 21, 2024,
Accepted Date:
July 26, 2024,
Published Date:
July 31, 2024
Crossref doi:
https://doi.org/10.37547/ajbspi/Volume04Issue07-05
Khamidova Farida Muinovna
Samarkand State Medical University, Department of Pathological Anatomy with a sectional course, Uzbekistan
Khusinova Firuza Azgar Kizi
Samarkand State Medical University, Department of Pathological Anatomy with a sectional course, Uzbekistan
Journal
Website:
https://theusajournals.
com/index.php/ajbspi
Copyright:
Original
content from this work
may be used under the
terms of the creative
commons
attributes
4.0 licence.
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American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
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VOLUME
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33-48
OCLC
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1121105677
Publisher:
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INTRODUCTION
Acne (L70, L73. 0.) is a chronic inflammatory skin
disease affecting the hair sebaceous follicles and is
caused by a variety of factors including genetics and
androgens. Neonatal acne (acne neonatorum) occurs
in the first four weeks of life, and infantile acne appears
between 3 and 6 months. These conditions may be
associated with high androgen levels in girls and boys
(1,7).
Acne can develop at any age and is often seen in
teenagers and young adults. Symptoms include
comedones, pustules and inflammatory nodules.
Microbial flora, in particular Cutibacterium acnes, plays
a
significant
role
in
pathogenesis,
causing
inflammation and infection.
Treatment for acne includes topical retinoids, benzoyl
peroxide, antibiotics and, in some cases, oral
contraceptives or isotretinoin. It is important to
consider antibiotic resistance and the potential
psychological effects of the disease (2,8).
Historically, acne has been known since ancient times;
its descriptions are found among the ancient Egyptians
and Greeks. Current understanding of the disease
emphasizes the importance of genetic and immune
factors in its development.
Acne is an inflammatory skin disease that can appear at
different points in life and is often associated with
genetic factors (1,2,3,4).
Neonatal, nodular cystic and conglobate acne have a
pronounced genetic predisposition, and acne after
adolescence is associated with a family history of acne
in 50% of cases.
Research has identified genetic markers associated
with acne, including apolipoprotein A1 and various loci
detected through genome-wide analyses. Several
genetic pathways, including PI3K/AKT/mTOR, may
regulate sebum production and inflammation, which
play a key role in the development of acne (5).
Acne severity scoring systems vary and may include
analysis of comedones, papules and pustules.
Immunity research has shown that inflammation in
acne can be caused by a variety of factors, including
skin microbes and innate immune responses.
The following clinical and morphological forms of acne
are distinguished:
L70.0- Common acne (acne vulgaris), L70.1 - Globular
acne, L70.2 Smallpox acne, Necrotic miliary acne, L70.3-
Tropical acne, L70.4-Children's acne, L70.5- Acne
excoriée, Excoriated acne, L70.5-Other acne, L70.9-
Acne, unspecified.
Acne Vulgaris is a globally common chronic
inflammatory disease of the hair and sebaceous
follicles. Although acne is not life-threatening, it can
cause scarring, irritation and serious psychological
problems, including depression. Our review examines
the various causes of acne and methods of treating
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them. Major pathophysiological factors include
excessive sebum production, hyperkeratinization, P.
acnes colonization, and inflammation. In diagnosing
acne, it is important to distinguish between
inflammatory and non-inflammatory forms of lesions.
Problems of antibiotic resistance require the
development of new treatments (12).
Epidemiological studies show that acne affects up to
80% of adolescents and young adults. The age at which
acne most often begins ranges from 14 to 16 years in
girls and 16 to 17 years in boys. However, although acne
affects men and women at approximately the same
frequency, severe forms are more common among
men (17,18,19,20,21,22).
The causes and mechanisms of acne development are
not fully understood, but they are believed to be
associated with a number of factors. These include
hormonal imbalance and hypersecretion of sebum,
changes in its chemical composition, follicular
hyperkeratosis and colonization of the skin by the
bacteria Propionibacterium acnes. An important role in
the development of acne belongs to the immune
response to the antigens of these microorganisms,
which activate neutrophils and phagocytes.
These cells stimulate the complement system through
Toll-like receptors (TLR2), resulting in the synthesis of
pro-inflammatory interleukins such as IL-8, TNF-
α, IL
-
1β
and IL-12. These interleukins activate cyclooxygenase,
which promotes the production of inflammatory
mediators, such as leukotriene B4 from arachidonic
acid. It has been established that leukotriene B4
activates monocytes, eosinophils, T-lymphocytes and
other cells that secrete hydrolytic enzymes that
destroy the wall of the sebaceous gland. This leads to
the release of the contents of the gland into the
surrounding tissues and causes the development of
inflammation at the site of the lesion (23,24).
Immunodeficiencies such as chronic granulomatous
disease (CGD) can aggravate skin conditions such as
folliculitis. CGD is a rare inherited disease caused by a
defect in the enzyme NADPH oxidase, which prevents
white blood cells from effectively killing pathogens.
Such patients may experience recurrent bacterial and
fungal skin infections, including folliculitis and acne.
Diagnosis of CGD involves specific tests for neutrophil
function, and treatment includes infection prevention
and immunomodulators (6,7,8).
Hidradenitis suppurativa, also known as acne inversus
or acne inversus, is a chronic inflammatory skin disease
affecting the hair follicles and is associated with acne.
The disease manifests in intertriginous areas and can
cause significant burden due to pain, itching, malodor,
and emotional distress. Treatment may include
antibiotics, antimicrobials, and surgical interventions
to control symptoms and prevent disease progression
(9,10,11).
A study by Ballanger et al shows a significant influence
of heredity on the development and course of acne. A
family history of acne (A+) is associated with earlier
onset of the disease, often before puberty, and
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increases the recurrence rate after isotretinoin
treatment. In addition, acne patients whose parents
also suffered from acne (M+ and M+F+) are more likely
to experience problems with retention lesions. This
highlights the role of genetic factors as an important
prognostic indicator in clinical practice in the diagnosis
and selection of treatment strategies for acne (15).
Modern research focuses on the genetic aspects of
acne,
indicating
that
genetic
predisposition
significantly influences the occurrence, clinical
presentation, course and effectiveness of acne
treatment. Acne is a polygenic disease, which means
that it does not follow the classical laws of Mednellian
inheritance (25,26).
There are many genetic markers associated with acne,
including polymorphisms in genes such as tumor
necrosis factor alpha, matrix metalloproteinases
(MMPs), tissue inhibitors of metalloproteinases
(TIMPs), interleukin-1, CYP17A1, CYP1A1, and others.
Research by Yaykasli K.O. showed that genotype
frequencies for matrix metalloproteinase-2 (MMP-2)
and TIMP-2 inhibitor polymorphisms were similar in a
Turkish population between acne patients and
controls. However, an imbalance between MMPs and
TIMP-2 may increase susceptibility to acne, as shown
for the TIMP-2 (-418 C/C) genotype, which was twice as
common in patients compared to controls (27).
Most of the genes studied in the context of acne play
key roles in innate immune function, skin lesion
formation, or steroid hormone metabolism. Particular
attention is paid to polymorphisms of genes involved
in the biosynthesis of androgens, including
testosterone, such as cytochrome P450c17α, encoded
by the CYP17A1 gene (28,29,30,31,32).
A study by N. Malikova et al. in the Uzbek population
showed that certain genotypic variants of the CYP17A1
gene are associated with a higher likelihood of
developing acne and its severe course. For example,
the heterozygous A/G genotype was typical for
patients with moderate acne, while the G/G genotype
was more common in patients with severe acne. The
A/A variant was protective and associated with a
reduced risk of acne (33,34).
In China, the CYP17-34T/C polymorphism was
associated with acne, with men with the homozygous
C/C variant and the C allele having a high risk of severe
acne, in contrast to women with mild to moderate
acne, where no such association was observed (35 ,36).
A polymerase chain reaction (PCR) study examined the
effect of CYP17 gene polymorphisms on the
development of acne in Chinese men. The homozygous
C/C variant and the C allele were found to be
significantly more common in men with severe forms
of acne compared to the control group, confirming
statistically significant differences. However, among
women with mild and moderate forms of acne, no
statistically significant differences were found with the
control group, indicating a possible sex difference in
the genetic predisposition to severe forms of acne.
Another study among Indonesian patients showed
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that polymorphisms in the CYP17A1, CYP1A1 and TNF-
α
genes did not correlate with the risk of developing
severe acne. However, it has been found that
polymorphisms in the CYP1A1 gene may contribute to
acne in general. These findings highlight the
complexity of the genetic background of acne and the
need for further research to determine the precise role
of these and other genetic factors in the development
of the disease (37).
Researchers in Germany found that having the GG
genotype of the CYP1A1 gene may increase the risk of
developing acne. This genotype is thought to
contribute to a deficiency of natural retinoids leading
to follicular hyperkeratosis and acne vulgaris. This may
also explain the high effectiveness of retinoids in the
treatment of severe acne in patients with this
polymorphism, since they show a better therapeutic
response than patients without this polymorphism
(38).
Studies have shown that the -308 G/A and -238 G/A
polymorphisms in the TNF gene are significantly more
common in patients with acne vulgaris, especially
those suffering from severe forms of acne, than in
healthy individuals. This is confirmed by the increased
risk of developing acne in the European population
compared to the Asian population. In addition, high
levels of the proinflammatory cytokine IL-8 and a
significant frequency of the IL-8-251T>A polymorphism
are found in Pakistani patients with acne, highlighting
a genetic predisposition to the development and
severity of acne (39,40,41,42).
In addition, analysis of the rs4646421 polymorphism of
the CYP1A1 gene showed that although the activity of
the cytochrome CYP1A1 enzyme is important for the
metabolism of sex hormones and vitamin A, a direct
connection
of
this
polymorphism
with
the
development of acne was not found. However, this
genetic marker has been shown to have significant
prognostic value for predicting severe acne, as patients
with severe acne are more than twice as likely to have
an unfavorable allelic variant as controls (43).
An increase in the level of TSPO in the skin of patients
with acne, along with other enzymes that metabolize
steroids -
3βHSD, CYP11A1, may indicate an
intensification of the synthesis of steroids in the skin
during this period. Pathology, as well as their
contribution to the development of chronic
inflammation in acne (50).
A study from Western Iran found that the PPARγ
Pro12Ala and C161T polymorphisms do not directly
influence the risk of developing acne vulgaris (AV), but
the PPARγ Pro allele is associated with increased
susceptibility to AV in adults over 20 years of age. In
addition, polymorphisms influence the lipid profile of
patients, indicating significantly higher levels of total
cholesterol and triglycerides in carriers of the variant
CG genotype compared to the CC genotype. The study
also found that CT and TT genotypes were associated
with lower serum cholesterol and LDL-C levels. These
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data highlight the importance of genetic factors in the
pathogenesis and clinical presentation of acne, as well
as their possible influence on the lipid profile, which
may have implications for the choice of acne treatment
strategy (16).
A study conducted among Turkish patients with acne
vulgaris found significant differences in the frequency
of the IGF-I (CA)19 genotype between affected and
healthy subjects, supporting its possible influence on
the development of acne (P=0.0002). This genotype
was also found to be associated with acne severity
(P=0.015), suggesting a role in disease progression in
this ethnic group (44,45).
Studies have also shown that tumor necrosis factor
alpha (TNF-
α), a powerful pro
-inflammatory cytokine,
plays a key role in triggering and regulating the
cytokine cascade in inflammation and the immune
response. One of the functional polymorphic loci, G-
308A, has a significant effect on the synthesis and level
of TNF-
α in the div, which emphasizes its potential
importance in the pathogenesis of acne and its clinical
course (46,47).
The authors concluded that elevated levels of
interleukin-8 and its genetic polymorphism IL-8-251T>A
may contribute to the development of acne in the
population. Genetic markers play a key role in the
development and progression of acne. A detailed study
of the genetic and immunogenetic factors associated
with acne may lead to a better understanding of the
molecular and genetic mechanisms of this condition.
This knowledge will help in the development of new
methods to predict the course of the disease and
effective therapeutic approaches to treat acne, taking
into account genetic polymorphisms (48,49).
The formation of scar tissue includes three phases that
follow in a certain time sequence: inflammatory,
proliferative and remodeling phase (51).
The main structural units active in the inflammatory
and proliferative phase are fibroblasts, capillary
endothelium, transform-transient growth factor (TGF)
β1 and β2, platelet
-derived growth factor (PDGF),
insulin-like growth factor (IGF-1) and epidermal growth
factor (EGF). Vascular endothelial growth factor
(VEGF), which is produced by epidermal cells, acts as a
positive regulator of angiogenesis. Tissue inhibitors of
metalloproteinases (TIMPs) are endogenous inhibitors
of matrix metalloproteinases (MMPs). Thus, increased
levels of TIMP are presumably associated with
hypertrophic scar formation. Tumor necrosis factor α
(TNF-
α) is an inflammatory cytokine produced by
monocytes and macrophages during the inflammatory
phase. This cytokine is known to cause collagen
degradation and help minimize excessive scarring (52).
During the remodeling phase, excess extracellular
matrix is degraded and type III collagen, the immature
form of collagen, is replaced by mature type I collagen.
TGF-
β3 is believed to play a leading role in this process.
Also, members of the MMP family have a significant
effect on the degradation and remodeling of the ECM
and mediate the degradation of collagen types I and III,
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reducing inflammation and neutralizing the effects of
chemokines (53).
Decorin is a proteoglycan component of cutaneous
connective tissue that binds to type I collagen fibrils
and influences TGF-
β. By binding and neutralizing TGF
-
β, decorin reduces the stimulating effect
of TGF-
β on
the
synthesis
of
collagen,
fibronectin
and
glycosaminoglycan. Decorin levels are reduced in
keloids and hypertrophic scars, and its antifibrotic
properties have attracted attention as a possible
therapeutic agent (54,55).
The role of periosteum (extracellular matrix protein),
the level of which is sharply increased in hypertrophic
scars and keloids compared to normal tissues, is also
actively discussed (56,57).
Proinflammatory factors such as interleukins IL-
1α, IL
-
1β, IL
-6, and tumor necrosis factor alpha are
upregulated in keloid tissues, suggesting that patients
with
keloids
have
increased
expression
of
proinflammatory genes in the skin. This may contribute
to chronic inflammation, which, in turn, can cause
invasive growth of keloids, although according to the
results of a study that was conducted in Turkey (90
people in the study group and 30 in the control group),
polymorphic variants
Ants TNF-
α (
-308 G/A) and IL-
1β (
-511 C/T) were not
associated with acne susceptibility, acne scarring, or
acne severity (58).
Increased expression of pro-inflammatory factors
means that keloids and hypertrophic scars are a
consequence of inflammatory processes in the
reticular layer of the dermis. Various external and
internal stimuli (local, systemic and genetic) after injury
can contribute to inflammation. The nature of these
irritants most likely determines the characteristics,
number, and development of keloids and hypertrophic
scars. In England, when studying a small group of
patients with keloid scars (including acne), they found
that the presence of HLADRB5 and HLA-DRB1*15 was
associated with keloid disease (59).
A meta-analysis of the association of the Arg72Pro
polymorphism of the P53 gene with keloid scars in the
Chinese population included the results of 6 studies,
which included 359 patients with keloid scars and 493
people. as a control. It was determined that the Pro
allele of the Arg72Pro polymorphism of the P53 gene is
a risk factor for the development of keloids in the
Chinese population compared to the Arg allele (OR =
2.29, 95% CI = 1.45
–
3.60) (60).
A study was conducted in China in which the first stage
analyzed 1056 patients with acne and 1056 controls
using high-density chips. At the second stage of the
study, in an independent cohort (1860 patients and
3660 people in the control group), 101 single
nucleotide polymorphisms were tested, of which 3
showed an association: rs747650 of the DDB2 gene and
rs1060573 (11p11.2), rs7531806 of the SELL gene
(1q24.2), which are involved in androgen metabolism,
inflammation, and scar formation in severe acne (61).
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Keloids develop in fibroproliferative disorders against
the background of chronic inflammatory processes in
the skin. A genome-wide association study showed an
association with rs8032158 in the NEDD4 gene. This
gene is expressed by neural progenitor cells and has six
different transcripts. Carriage of the rs8032158 risk
allele C in patients with keloids is associated with
selectively higher expression of type 3 transcript (TV3
NEDD4) and activation of the NF-
κB pathway. The
analysis revealed that NEDD4 TV3 is involved in NF-
κB
activation through its association with the adapter
protein RIP. These results suggest that NEDD4 TV3 is a
potential diagnostic marker and therapeutic target for
chronic skin diseases, including keloid (62).
A genome-wide association study of 478 African
Americans (122 cases, 356 controls) was conducted in
the USA in 2014. An association was found with the
q21.2-22.3 locus on chromosome 15, which includes the
NEDD4 gene. This gene has previously been shown to
be associated with keloid scars in Japanese and
Chinese populations. But in African Americans, a more
significant association was found with the MYO1E
gene. In addition, an association was established with
the q13.5 locus on chromosome 11 (MYO7A gene,
rs35641839, OR = 4.71, 95% CI 2.38
–
9.32, p = 8.34 × 10
–
6). The authors suggest that the identification of
polymorphisms associated with the formation of
keloid scars in two myosin genes indicates that the
altered cytoskeleton contributes to enhanced
migratory and invasive properties of keloid fibroblasts
(63).
Long non-coding RNAs (lncRNAs) are believed to play
a significant role in human diseases. Studies have
shown that overexpression of long non-coding RNA
AC067945.2 did not affect cell proliferation in
hypertrophied scar tissue, but promoted early
apoptosis in normal skin fibroblasts. Except Moreover,
overexpression
of
AC067945.2
inhibited
the
expression of COL1A1, COL1A2, COL3A1 and α
-SMA
proteins. In turn, TGF-
β1 can inhibit t
he expression of
AC067945.2. In the group with overexpression of
AC067945.2, 138 mRNA expression differed from the
control group, of which it was increased in 14 and
decreased in 124. Overexpression of AC067945.2
correlated with developmental processes, binding,
extracellular region and the VEGF and Wnt signaling
pathways. The study revealed the functions of the
novel lncRNA AC067945.2, which may help understand
the mechanisms regulated by AC067945.2 in the
pathogenesis of hypertrophic scars (64).
Overexpression of long non-coding RNA ncRNA8975-1
was found in hypertrophic scars and skin fibroblasts.
Overexpression of lncRNA8975-1 prevents cell
proliferation and reduces the expression of COL1A2,
COL1A1, COL3A1 and α
-SMA in hypertrophic scar
fibroblasts, whereas knockdown of lncRNA8975-1 has
the opposite effect. Further studies of the mechanisms
by which lncRNA8975-1 expression is regulated may
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lead to a better understanding of the pathogenesis of
hypertrophic scars (65).
The study of the genetic aspects of the problem of scar
formation after acne, as well as the determination of
molecular genetic markers of this condition, is almost
at the very initial stage. It is likely that this gap will be
filled in the coming years, which will provide impetus
for the development of new effective means of
preventing and treating this disease (71). regulators of
androgen receptors - 25-OH-VD, cytochrome p 450 (17-
alpha hydroxylase), insulin-like growth factor are
important in the pathogenesis of rapid non-genomic
molecular cellular reactions of peripheral androgen
metabolism and, in the future, may determine new
algorithms for the diagnosis and treatment of acne
diseases (66).
An important aspect of acne pathogenesis is the
participation of keratinocytes in the inflammatory
response. C. acnes activates Toll-like receptor (TLR)-2
and TLR-4 on keratinocytes, leading to activation of
signaling cascades including the NF-
κB pathway and
the MAPK pathway. Subsequently, keratinocytes
produce IL-1, IL-8, IL-6, granulocyte-macrophage
colony-stimulating factor (GM-CSF), TNF-
α, matrix
metalloproteinases (MMPs) and human β
-defensin-2
(hBD-2). In addition to TLR-2 and TLR-4, the CD36
receptor expressed on keratinocytes is also involved in
the recognition of C. acnes.
Once C. acnes CD36 is detected, keratinocytes begin to
synthesize reactive oxygen species (ROS), especially
superoxide anion, generated from the cytosolic
enzymes NAD(P)H oxidases. These ROS provide an
antibacterial effect and trigger an inflammatory
response. Analysis of identified variants of the
nucleotide sequence of keratinocyte proliferation and
differentiation genes showed that severe acne is likely
associated with polymorphic loci AP3B1, FERMT1,
FERMT3, GBA, SUFU (67).
Data on the role of family history and possible
inheritance of acne have been confirmed in a number
of studies on familial cases of this dermatosis, its more
frequent development in monozygotic twins, but the
significance of genetic associations is not fully known.
Thus, He L. et al. (2014) revealed a connection between
acne and TP63, which ensures the regulation and
differentiation of epithelial stem cells (68).
In another study, the authors suggested an
association of acne development with LGR6, which is a
mediator of the WNT signaling pathway and ensures
the functioning and differentiation of sebaceous gland
stem cells. Additional associated genes were LAMC2,
encoding a major component of the basement
membrane, and SPECC1L, encoding a cross-linking
cytoskeletal protein that plays an important role in cell
adhesion and migration (69).
It has been shown that the presence of the disease in
first-degree relatives may be a risk factor for the
development of dermatosis. A case of identification
and determination of the significance of polymorphism
of the NCF1, CD3E, ORAI1, IGHM, TAZ genes in patients
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with severe forms of the disease with a family history
is presented. The conducted studies revealed identical
allelic variants in five genes: NCF1, CD3E, ORAI1, IGHM,
TAZ in two closely related patients (father and son)
with severe acne. Polymorphisms of the studied genes
probably influence the development of an imbalance in
the oxidase system, the functioning of mitochondria,
reduced proliferation of T cells, as well as the
formation of an imbalance in the secretion of
immunoglobulins. The data obtained may be factors in
the torpid course of severe dermatosis, which
determines the need for further research (70). Based
on the analysis of literature data, it can be noted that
in our Republic of Uzbekistan, the prognostic values,
features and role of the NLR and TLR2 genes, and their
relationship in the development of acne have not been
fully studied.
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НОВЫЕ
ПАТОГЕНЕТИЧЕСКИЕ
ФАКТОРЫ
АНДРОГЕНЗАВИСИМЫХ
ДЕРМАТОПАТИЙ.
д.м.н. Азимова Ф. В., Ходжаева М. Б.
International Academy Journal Web of Scholar
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67.
ПАТОГЕНЕТИЧЕСКАЯ
РОЛЬ
АЛЛЕЛЕЙ
ПОЛИМОРФНЫХ
ВАРИАНТОВ
ГЕНОВ
ПРОЛИФЕРАЦИИ И ДИФФЕРЕНЦИРОВКИ
КЕРАТИНОЦИТОВ ПРИ ТЯЖЕЛОЙ СТЕПЕНИ
АКНЕ.Демина О.М., Международный научно
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исследовательский журнал
▪
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1 (127)
▪
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He L. Two new susceptibility loci 1q24.2 and
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p. 2870.
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Petridis
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Genome-wide
meta-analysis
implicates
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hair
follicle
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РОЛЬ ГЕНЕТИЧЕСКИХ ФАКТОРОВ ПРИ
СЕМЕЙНОМ СЛУЧАЕ АКНЕ О. М. Демина, А.
Г. Румянцев, Н. Н. Потекаев.ВЕСТНИК РГМУ
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