CC BY
11
Azimova Fatima Vahidovna, The head of the scientific department of dermatocosmetology of the Republican specialized scientific and practical medical center of dermatology and venereology
Sabirov Ulugbek Yusupkhanovich, Director of the Republican specialized scientific and practical medical center of dermatology and venereology Shorakhmedov Shorahmat Shorasulovich, Scientific employee of the department of dermatocosmetology of the Republican specialized scientific and practical medical center of dermatology and venereology
E-mail: [email protected]
MARKERS OF FACTORS OF GROWTH AND APOPTOSIS IN FORECASTING THE CURRENT OF NEST ALOPECION
Abstract: Markers of growth factors and apoptosis in patients of the Uzbek population with alopecia areata as risk factors for the development of severe forms of the disease. Molecular genetic studies of patients with alopecia areata revealed the prognostic value of the polymorphisms G (-634) C and G (-1154) A of the VEGF G-308A gene of the TNF-a gene. Genobiological ensembles of these polymorphisms with growth factors and apoptosis were determined, on the basis of which markers determining the severity of the pathological process were identified.
Keywords: alopecia areata, polymorphism, genes, non-scarring alopecia.
In modern dermatocosmetology, there is a tendency sis, which play an important role in the phases of anagen to increase the incidence of skin of the scalp, in particu- and telogen in alopecia [5, 7, 6]. lar, hair loss - non-scarring forms of alopecia. Despite Purpose of the study: Revealing of markers of
the long history of the problem of non-scarring forms of growth factors and apoptosis in patients of the Uzbek alopecia, the issues of etiopathogenesis, diagnosis and population with nest allopathy as risk factors for the de-treatment of non-scarring alopecia have not been suffi- velopment of severe forms of the disease. ciently studied yet [1,2]. The main share of non-scarring Materials and methods: 67 patients with alopecia hair loss is nested alopecia. As a pronounced cosmetic nest at the age of 14 to 50 years were monitored, 52.8% defect, alopecia alopecia often leads to psychoemotional were men, 47.2% were women who were on inpatient discomfort, which reduces the quality of life, and causes and outpatient care at the clinic of the Republican Spe-both social problems caused by restrictions in the choice cialized Scientific and Practical Medical Center of Der-of profession, employment and social prospects, and eco- matology and venereology. Molecular genetic studies in nomic, due to the length of treatment and its high cost. patients with non-scarring forms of growth factor alo-In 5-10% of patients with small focal form of the disease, pecia and apoptosis was performed by real-time PCR. complete hair loss on the scalp (total form) develops, and To assess the differences in the values of biochemical or in 1-2% of cases - complete hair loss on the head and clinical parameters between carriers of different geno-trunk (universal form) [3, 4]. Curing the universal form types, the Mann-Whitney U test or the Student's t-test of alopecia areata in less than 10% of cases. for independent elections was used for the investigated
Multicentre studies in the field of molecular genetics genes. The value of P < 0.05 was taken as statistically have revealed many genes of growth factors and apopto- significant. Prognostic efficiency of genetic markers was
Section 5. Medicine
determined by the standard AUC-classifier. The correlation relationships of growth factor polymorphisms and apoptosis with FGF, PDGF, FAS molecules were determined based on the Kendall rank correlation coefficient.
Results and discussion. Patients with focal form were 36.2%, polychial - 29.7%, ribbon-shaped - 1.9%. The heavier forms were recorded to a lesser extent and differed in the torpid current: 16.1% in the subtotal form, 4.5% in the total form, and 18 in the universal form (11.6%). The percentage of women in the study is 16.2% higher, because the immune system of women is more labile than that of men. 38.6% ofpatients had lesions of the nail plates ofthe hands: dystrophic changes, small-point indentations of the "thimble" type, pronounced longitudinal striation combined with the dim color of the plates themselves. Onychodystrophy depended on the severity of alopecia and was more often observed in patients with total and universal forms of the disease. In 71.6% of patients with alopecia areata there was a progressive stage of the disease, which was characterized by a "zone of shaky hair" around the foci (with easy sipping of hair along the edge of the focus, their painless epilation occurs). In 27.1% of patients, there was a growth of hair follicles (velus) in the focus of alopecia against the background of the progress of the pathological focus. The stationary stage of alopecia areata was noted in 23.9% of patients, regressing stage - in 4.5%. In 7,5% ofpatients there were subjective sensations in the form of hypersensitivity of the skin, paresthesias and erythema, preceding the appearance of a new focus of hair loss. Relapses of the disease occurred in 68.2% of patients, the duration of the intervals between the occurrence of new foci is variable. Analyzing the duration of the disease, the largest part of the patients suffered nest alopecia before 1 year (43.8%) and from 1 year to 5 years -38.7%. Longer terms of the disease were observed in 1/5 of patients (17.5%). Diseases of the thyroid gland in the form of diffuse goiter ofvarious degrees (51%), as well as iron deficiency anemia (32.9%) and gastrointestinal tract diseases (27.7%) represented the concomitant pathology of patients with alopecia areata.
Previously, in our studies, a method for testing the G (-634) C and G (-1154) A polymorphisms of the VEGF gene based on real-time PCR in patients with alopecia areata and individuals of the control group was modified and tested. The observed distributions of heterozygous genotypes of both loci reliably corresponded to the ex-
pected law for the Hardy-Weinberg equilibrium. Because the frequency of heterozygosity of polymorphisms is not very high, their prognostic value was also low (AUC = 0.57 and 0.54, respectively), which indicated the non-independence of these loci in the development of alopecia. According to the calculated odds ratio, the probability of development of angiogenesis disorders in patients with alopecia was more than 3.5 times higher than in the control group (OR = 3.9, 95% CI 0.33238, 46.17) with a level of x2 = 1.2 and P = 0.2. Molecular genetic studies of tumor necrosis factor (TNF-a) polymorphism revealed the detection of the homozygous genotype of the muta-tion-AA G-308A polymorphism of the TNF-a gene in 3.6% of cases, while in the control group this factor was 2.9%. In the group of patients with alopecia, a heterozygous genotype of the TNF-a (G-308A) - G/A mutation was found with a corresponding incidence of 32.1%. In the control sample, those carrying the mutant allele A were 8.6%. These differences are statistically significant and indicate the association of G-308A polymorphism of the TNF-a gene with the development of alopecia. Carrying of allele A and heterozygous genotype G/A is reliably associated with an increased risk of developing the disease (x2 = 4.4, P = 0.036, OR = 3.2, 95% CI = =1.033, 9.772 and x2 = 5.6; P = 0.018, OR = 5.05, 95% CI = 1.216-21, respectively). Allele G and genotype G / G, in contrast, are protective markers.
But the most informative in predicting the course of alopecia areata is the detection of markers predicting the course ofthe disease by identifying correlation. Therefore, in order to reveal the relationship in patients with alopecia between the investigated genotypes of growth factors and apoptosis with FGF, PDGF, FAS, and a correlation analysis was performed, which showed interesting data.
Correlation analysis of fibroblast growth factor with endothelial growth factor and tumor necrosis factor polymorphisms in patients with alopecia areata showed a significant negative correlation of FGF with genotype GA of polymorphism G (-1154) A of the VEGF gene and a correlation trend with the remaining polymorphism of both genes (Fig. 1). It is supposed that the detection of this genotype of the VEGF gene in patients with alopecia areata proves a decrease in the concentration of fibroblast growth factor, which is a key factor in the realization of the cell cycle of the hair follicle, and indicates a severe course of the disease.
FGF in alopecia areata
О 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 О ООО ООО-Основной О 000 000 0 000 000
Основной
¡
I
Основной
Основной
I I *
1
-Основной
2
I
-Основной
G-634C G-634C G-1154 G-1154 G-308A G-308A G-308A (GG) (GC) A (GA) A(GG) (GG) (GA) (AA)
FGF in androgenic alopecia
Основно
у
¡Л Основной
I g
0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000
2 []
IÍJ
#
KS?
и £
1 I S; i 0 ' J (]
и
Й
i £ П 4 T1
jgr & jf # #
СГ Q> , ,V ü tí V
Figure 1. Correlation analysis of fibroblast growth factor with endothelial growth factor and tumor necrosis factor polymorphism
The correlation analysis of platelet growth factor with the indices of endothelial growth factor and tumor necrosis factor polymorphisms in patients with alopecia nest showed only the correlation tendency of both negative and positive of this growth factor with
all the polymorphisms of the investigated genotypes (Fig. 2). Presumably, platelet-derived growth factor is not significant for endothelial growth factor and tumor necrosis factor polymorphisms and is not a marker of the course of the disease.
pdgf in alopecia areata
0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000
2 g 2
/J-Основной
I
Основной
я
Ml
>>ОСНОВНОИ r J
i.
^ -Основной^ '' - ^
Основной fj
-Основной
G-634C G-634C G-1154 G-1154 G-308A G-308A G-308A (GG) (GQ A (GG) A(GA) (GG) (GA) (AA)
pdgf in androgenic alopecia
2
-Основной
0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000
1 и
[]
г 1 1] 'J
jrJ {] \
2
í
\ ¡
1]
^ # # # & # & 4
b' <s b'
ь <ь ,V
о о
Figure 2. Correlation analysis of platelet-derived growth factor with indicators of endothelial growth factor and tumor necrosis factor polymorphisms
Section S. Medicine
The highest correlation analysis results with endothelial growth factor and tumor necrosis factor polymorphism in patients with alopecia areal showed the FASL apoptosis factor (Fig. 3). Thus, a significant positive correlation is observed between this factor and the
genotype of G polymorphism of the G (-634) C gene of the VEGF gene and a negative significant correlation with the GG genotype of the G (-308) A gene of the TNF-a gene in patients with nested alopecia.
FASL in androgenic alopecia
0 000 000 0 000 000 0 000 000 0 000 000 0 000 000 0 000 000
Основной
¿Основной Основной
Ъ ъ У,
I
[]
Основной
^Основной
г.
tí
jír
tí
tí3 tí tí
fas Lin alopecia areata
0 000 000 О 000 000 О 000 000 О 000 000 О 000 000 О 000 000 О 000 000 О 000 000
[]
1] I] Í1
i 1J __ V 0 s
2 £ I
11 []
I]
«sr
tí
гУ?
tí
А V
J?
.у
tír
¿4
$> л?
tí tí tí
Figure 3. Correlation analysis of the apoptosis factor with indicators of endothelial growth factor and tumor necrosis factor polymorphisms
With the remaining indicators of the polymorphism of the studied genes and FASL, there is a tendency to correlate. Apparently, the detection of the G genotype of the G (-634) C polymorphism of the VEGF gene indicates an increase in FASL apoptosis in patients with alopecia areata, which translates the cycle of the hair follicle from the anagen phase into telogen, is an unfavorable marker and indicates a severe course of the disease. Persons with this marker are prone to a more severe course of alopecia areata. In contrast, the detection of the GG genotype by the G (-308) A polymorphism of the TNF-a gene is a favorable marker of the course of alopecia areata and observes a decrease in the FASL apoptosis factor and a lighter course of the disease.
Conclusions: Identification of genobiological ensembles between FGF and genotype GA of polymorphism G(-1154) A of the VEGF gene (significant negative correlation), FASL with genotype G (-634) C polymorphism of the VEGF gene (significant positive correlation) and GG genotype of polymorphism G (-308) A of the TNF-a gene (significant negative correlation), a pathogenetic relationship of the genotypic variants of VEGF and TNF-a with growth factors and apoptosis in alopecia are established. These genotypes can be considered markers of nesting alopecia in people of the Uzbek population and used to predict the course of this pathology and prevent the development of severe torpid forms of the disease.
References:
1. Адаскевич В. П., Мяделец О. Д., Тихоновская И. В. Алопеция. - М.,- 2000.- 187 с.
2. Гаджигороева А.Г. Болезни волос: классификация. Нерубцовые алопеции // Дерматология.- 2008. - № 1.-С. 25-26.
3. Вгеуег В., Vanichakarn Р., Szatkowski J.P., Park J.Y., He T. Osteogenic Activity of the Fourteen Types of Human Bone Morphogenetic Proteins (BMPs) // J Bone Joint Surg Am.- 2003.- Vol. 85.- P. 1544-1552.
4. Clark A. F. Synergistic Signaling from Extracellular Matrix-Growth Factor Complexes. Journal of Investigative Dermatology.-2008.- Vol. 128.- P. 1354-1355.
5. Kozlowska U., Blume-Peytavi U., Kodelja V. Expression ofvascular endothelial growth factor (VEGF) in various compartments of the human hair follicle // Arch Dermatol Res.- 1998.- Vol. 290.- P. 661-668.
6. Simonetti O. Expression of vascular endothelial growth factor, apoptosis inhibitors (survivin and P. 16) and CCL27 in alopecia areata before and after diphencyprone treatment: an immunohistochemically study // British Journal of Dermatology.- 2004.- Vol. 150.- No. 5.- P. 940-948.
