Научная статья на тему 'Vitamin D receptor gene polymorphism among children'

Vitamin D receptor gene polymorphism among children Текст научной статьи по специальности «Клиническая медицина»

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Ключевые слова
vitamin D / children / bone metabolism / gene polymorphism / витамин D / дети / костный метаболизм / полиморфизм генов

Аннотация научной статьи по клинической медицине, автор научной работы — А.К. Жумалина, Б.Т. Тусупкалиев, И.С. Ким, М.Б. Жарлыкасинова

The literature review presents modern data on the role of gene polymorphism VDR (rs1544410, rs2228570), RANKL (rs 9594738, rs9594759) in the pathogenesis of vitamin D deficiency. and a practical interest in pediatrics, therapy and gerontology.

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Полиморфизм генов рецептора витамина D у детей

В литературном обзоре представлены современные данные о роли полиморфизма генов VDR (rs1544410, rs2228570), RANKL (rs 9594738, rs9594759) и их роль в патогенезе дефицита витамина D. Показано, что поиск генетических маркеров молекул, влияющих на начало и особенности течения дефицита витамина D, представляет теоретический и практический интерес в педиатрии, терапии и геронтологии.

Текст научной работы на тему «Vitamin D receptor gene polymorphism among children»

Receivedby the Editor 18.11.2020

IRSTI 76.29.47, 31.27.35 UDC616-053.2:575.174.015.3:577.161.2.

VITAMIN D RECEPTOR GENE POLYMORPHISM AMONG CHILDREN

A. Zhumalina, B. Tusupkaliev, I. Kim, M. Zharlykasinova

Non-commercial joint stock company«West Kazakhstan Marat Ospanov medical university», Aktobe city, Kazakhstan

The literature review presents modern data on the role of gene polymorphism - VDR (rs1544410, rs2228570), RANKL (rs 9594738, rs9594759) in the pathogenesis of vitamin D deficiency. and a practical interest in pediatrics, therapy and gerontology.

Key words: vitamin D, children, bone metabolism, gene polymorphism.

ПОЛИМОРФИЗМ ГЕНОВ РЕЦЕПТОРА ВИТАМИНА D У ДЕТЕЙ

Жумалина А.К., Тусупкалиев Б.Т., Ким И.С., Жарлыкасинова М.Б.

Некоммерческое акционерное общество «Западно-Казахстанскиймедицинский университет имени Марата Оспанова», Аатобе, Казахстан

В литературном обзоре представлены современные данные о роли полиморфизма генов - VDR (ге1544410, ге2228570), RANKL (ге 9594738, ге9594759) и их роль в патогенезе дефицита витамина D. Показано, что поиск генетических маркеров молекул, влияющих на начало и особенности течения дефицита витамина Б, представляет теоретический и практический интерес в педиатрии, терапии и геронтологии.

Ключевые слова: витамин D, дети, костный метаболизм, полиморфизм генов.

БАЛАЛАРДАГЫ Д ВИТАМИНШЩ ГЕНД1К РЕЦЕПТОРЫНЬЩ

ПОЛИМОРФИЗМ1

Жумалина А.^., Тусшкалиев Б.Т., Ким И.С., Жарлыкасинова М.Б.

«Марат Оспанов атындагы Батыс ^азакстан медицина университет» Коммерциялы; емес акционерлш когамы, Актебе к., ^азакстан

Эдеби шолуда D дэрумеш тапшылыгыныц патогенезiндегi VDR (rs1544410, rs2228570), RANKL (rs 9594738, rs9594759) гендiк полиморфизмнiн релi туралы заманауи мэлiметтер келтiрiлген ал ол педиатрия, терапия жэне геронтологиягада практикалы; кызыгушылыкты керсетедi

Тушнд1 сездер: D дэрумеш, балалар, CYЙек метаболизмi, гендiк полиморфизм.

Objective

Determination of the role of D - vitamin status, features of allelic gene polymorphism - VDR (rs1544410, rs2228570), RANKL (rs 9594738, rs9594759) and their part in the bone metabolism of children.

Materials and methods

A literature search was carried out in the eLibrary, GoogleScholar, Pubmed, Web of Science databases. Search depth is the last 10 years, from 2010 to 2020.

The review included publications in Kazakh, Russian and English languages. The selection of sources across databases was distributed in the next way (fig.1).

Number of WebofScience publications - 75

Number of Pubmed publications- 151

Number of eLIBRARY publications-132

Number of potentially relevant articles -72

Figure 1 - Scheme of literature review conducting.

The relevance of the problem associated with vitamin deficiency in the body, macro- and microelements, arising mostly due to violation of their intake, assimilation or excessive losses, is beyond doubt. Recently, more and more attention is paid to the problems of mineral metabolism (osteopathies). In connection with the steady increase in the number of osteopathies among children and adolescents, primarily osteoporosis, great importance is attached to assessing health status in terms of age, especially during critical periods of growth, one of which is the first three years of life, which includes the neonatal period [1].

Taking into consideration the fact that the mother's body is the environment for the unborn child, adverse factors, that affect the pregnant woman, can lead to impaired fetal development, enhance the bone skeleton formation abnormalities and bone mineralization even in the prenatal period. Macro- and microelements, vitamins are stored by the fetus in the last months of pregnancy, and it is very difficult tocompensate their deficiency in the postnatal period [2]. There is a large number of publications pointing out that pregnant women are deficient in micro- and macroelements [3,4]. There are studies focused on the study of bone metabolism in older children and adolescents [5], while this problem has not practically been studied in newborns and young children with prenatal calcium deficiency. Bone system diseases of children and adolescents pose a serious threat to the population, since insufficient bone mineralization in childhood can manifest itself in the form of osteoporosis many years later and even in adulthood. For instance, in the United States, about 10 million people suffer from osteoporosis, and a bone mass decrease is observed in another 18 million. There is no reliable data on the prevalence of osteoporosis among young children in Kazakhstan.

It can be assumed that violations of mineral metabolism in bone tissue occurs at the time of its formation in the womb due to abnormalities of the mineral transport through the placenta, or because of their initial deficiency in a pregnant woman. 17% of pregnant women with a normal pregnancy, 23 months before the deliveries, suffer from nonspecific symptoms of calcium deficiency: paresthesias, convulsive twitching, muscle contractions, bone pain, gait changes, etc. These symptoms are found almost five times more often among women with complicated pregnancy. Mineral metabolism abnormalities during pregnancy affect woman's bone and dental tissue. The situation gets aggravated if the mother breastfeeds the baby.

However, there is not enough data in the literature to help predict bone disorders in children with normal pregnancy and its complications. Also,methods of early diagnosis of bone metabolism dysfunction among children, in particular among newborns, are not used.

Bone mineralization problems during the neonatal period can interfere with normal skeletal development and formation, and prevent the achievement of optimal, genetically predetermined peak bone mass and density in later childhood.

Regarding the problem of the mineral metabolism formation among children of the first week of life, there are still many unclear, unexplored and contradictory aspects. There is no doubt that early diagnosis and prevention of bone mineralization disorders is one of the main pools for reducing mineral metabolism disorders and diseases in later age periods.

The skeletal system of newborns and young children is characterized by a number of features: the presence of a large amount of cartilage tissue, the reticular structure of bones, a rich vascular network in

the neck of the bone, and a significant thickness of the periosteum [6]. In the first months and years of life the development of the skeleton is proceed at the same time as multiple restructuring of the bone tissue does, reflecting its phylogenesis. Intensive growth with simultaneous remodeling creates a completely special position for bone tissue, where it is especially sensitive to adverse environmental influences, namely: nutritional disorders, regime of child's motoractivity, muscle tone, etc [7].

In modern conditions, the determination of the activity of osteogenesis and the rate of bone tissue remodeling is carried out through a quantitative analysis of a number of biologically active compounds - regulators of bone metabolism in the blood serum - levels of calciotropic hormones (parathyroid hormone (PTH), calcitonin (CT)), vitamin D metabolites (calcidiol, calcitriol) along with the determination of the content of vitamin D binding protein (VDBP - vitamin D bindingprotein) and the obligatory accounting of such biomarkers' dynamic content as alkaline phosphatase (ALP), osteocalcin (OK), osteoprotegerin (OPT), sRANKL is a soluble ligand RANK (receptor activator of nuclear factor -kB), C-terminal telopeptides of collagen type I [8,9]. However, the diagnostic and prognostic significance of most of these osteogenesis biomarkers was determined until recently only in adult patients and older children [9,10]. In this regard, it is obvious that the diagnosis of disorders of bone metabolism in childhood, in particular in newborns and children of the first year of life, including the determination of markers of osteogenesis, as well as the introduction of effective measures for their prevention, is one of the important tasks of pediatrics.

One of the main factors affecting calcium and phosphorus metabolism, which helps to ensure proper levels of these minerals for metabolic functions and bone mineralization, is vitamin D. The two main forms of vitamin D are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D is formed from 7-dehydrocholesterol (7-DHHS) via the intermediate pre-vitamin D3 when exposed to sunlight with a wavelength of 290-315 nm. Vitamin D3 comes from animal products, mainly fish oil, and vitamin D2 comes from plant foods. Vitamins D2 and D3 in their chemical formula have structural differences only in the side chain, however, they do not affect metabolism, and both forms have the functions of a prohormone [11].

Excessive sun exposure destroys Pre-Vitamin D3, preventing excess production of the "sun" vitamin. The liver converts vitamin D3 via the enzyme 25-hydroxylase (CYP27A1, CYP2R1) to 25 (OH) D (calcidiol). Mitochondrial CYP27A1 and microsomal CYP2R1 are the two main enzymes involved in C-25 hydroxylation, although there are several CYP enzymes with 25-hydroxylase activity but with higher Km and lower Umax. The most controversial is the question of the level that indicates a sufficient supply of vitamin D. There are two points of view assuming presence of vitamin D sufficient supply - the level of calcidiol 20 ng/ml and 30 ng/ml. Since February 2018, Russia has been implementing the National Program "Vitamin D Deficiency among Children and Adolescents in the Russian Federation: Modern Approaches to Correction" [12], which states that the calcidiol range from 30 to 100 ng / ml is sufficient. The range - 20-30 ng / ml is characterized as insufficient supply, and the level of 25 (OH) D less than 20 ng / ml indicates a deficiency of vitamin D in the child's body [12,13]. Serum level 25 (OH) D (1 ng / ml = 2.5 nmol / L) is a criteria for laboratory assessment of vitamin D deficiency [14,15]. 25 (OH) D is further converted in the kidneys by the enzyme D-1-a-hydroxylase (cytochrome P450, CYP27B1) into metabolically active vitamin D - 1 a, 25 (OH) 2D (calcitriol). This enzyme is also called renal 1a-hydroxylase, as it was first found in the kidneys. The synthesis of 1 a, 25 (OH) 2D in the kidneys is regulated by several factors: the level of phosphorus and calcium in serum, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), as well as the concentration of 1 a, 25 (OH) 2D itself serum [15]. Many tissues have local 1-a-hydroxylases: bones, placenta, prostate gland, skin, macrophages, T-lymphocytes, dendritic cells, some cancer cells, parathyroid glands. Depending on the presence of 25 (OH) D, cells can produce biologically active Vitamin D using their local 1-a-hydroxylases. 1 a 25 (OH) 2D is structurally similar to steroid hormones [16,17] and, through the feedback mechanism, regulate their own synthesis, and also reduce the synthesis and secretion of PTH in the parathyroid glands (Fig. 2). The vitamin D hormone induces its own destruction hormone by activating 24-hydroxylase (CYP24A1), which catalyzes multistep catabolism of both 25 (OH) D and 1 a, 25 (OH) 2D to form biologically inert water-soluble compounds, including calcitric acid [16,18]. 1 a 25 (OH) 2D increases the efficiency of intestinal calcium absorption from 10-15% to 30% due to interaction with VDR-RXR

and, thereby, ensures the functioning of epithelial calcium channels and calcium-binding protein. As a result of experimental studies on animals, it was found that 1a, 25 (OH) 2D also increases intestinal absorption of phosphorus from 50-60 to 80% [17,18].

Since the discovery of vitamin D, or "sun vitamin", it has only been considered in terms of calcium-phosphorus metabolism. However, the results of numerous studies in recent years have shown that vitamin D in the hormonally active form 1 a, 25-dihydroxyvitamin D (1 a, 25 (OH) 2D; calcitriol) has a number of effects not related to the skeletal system. The steroid hormone vitamin D, its receptor (VDR) and metabolizing enzymes involved in the co-production of biologically active forms of the hormone are the main participants in the D-endocrine system. This system plays an

Fig. 2 - Vitamin D metabolism. important role not only in bone metabolism, including calcium absorption in the intestine, but also in metabolic pathways that are involved in immune system responses and carcinogenesis [19]. It participates in maintaining the modulation of inflammatory responses, the immune response, and cell growth and differentiation. In the immune system, for instance, vitamin D promotes monocyte differentiation and inhibits lymphocyte proliferation and the secretion of cytokines such as interleukin-2, interleukin-12, and interferon-y. In recent literature, there is information about the effect of vitamin D deficiency on the development of autoimmune diseases, diabetes mellitus,

oncological diseases, in particular breast cancer, prostate cancer, colorectal cancer [11,20]. Vitamin D has antiproliferative effects on several different types of cancer cells [21].

The active metabolite of vitamin D3 is calcitriol, which realizes its endocrine, paracrine and autocrine biological effects [22]. The biological action of 1a, 25 (OH) 2D is carried out by binding to vitamin D receptors (VDR), which are localized in most cells and tissues [14,16]. Vitamin D receptors have been identified in more than 35 target tissues that are not involved in bone metabolism [23]. Some of them are endothelium, pancreatic insular cells, hematopoietic cells, myocardium and striated muscles, monocytes, neurons, placental cells and T-lymphocytes, which confirms the pleiotropic effect of vitamin D3 [24]. It was calculated that exposure to vitamin D receptors directly and / or indirectly changes the expression of a large number of genes (0,5-5% of the total human genome, that is, 100-1250 genes) [18].

The vitamin D receptor is an organized structure that alters the transcription of genetic material when it interacts with a 1a, 25 (OH) 2D molecule. The presence of the vitamin D receptor was proven in 1974 [25], which allowed an intensive study of its biochemical characteristics. Cloning of this receptor and subsequent analysis of recombinant proteins made it possible to approach the key points in understanding the structure and function of the receptor [26]. The vitamin D receptor protein is

made up of three distinct regions: the N-terminal DNA-binding domain, the C-terminal ligand-binding domain, and a large unstructured region that links functional protein domains together. The C-terminal region of the molecule, the three-dimensional structure of which was described using X-ray crystallography [27], is a complicated complex that includes 12 a-helices. The contact amino acids in these subsets of the a-helices are the substrate for dynamic ligand binding. It is important that the selective binding of 1,25 (OH) 2D leads to the formation of two independent protein interactions on the surface of the vitamin D receptor. One of them improves activation of certain genetic loci, the products of protein expression, which are the key to the activity of 1a, 25 (OH) 2D.

Today medicine is focused on preventive therapy - prevention and diagnosisin time are the key to human health, being the main issues of the medical community. The risk of developing a specific disease can be predetermined from the very birth of a patient using molecular genetics [44]. This is due to the fact that human diseases are more or less associated with signs of heredity. Diseases are able to be a consequence of mutations of one allele of a gene (dominant), a combination of mutations in two alleles: recessive and multifactorial combinations, so-called polygenic diseases [28]. Genetic polymorphism is the diversity of the frequencies of the alleles of homozygotes. Differences between alleles of the same gene, as a rule, consist in minor variations in its genetic code. Most of genetic polymorphism is provided by replacements of one nucleotide to another and changes in the number of repeated DNA fragments. This is due to the fact that human diseases are more or less associated with the characteristics of heredity [29]. Practical usage of knowledge about the existence of "predisposition genes" of mutant alleles, which are compatible with the normal life support of the organism in the postnatal period, makes it possible to predict the course of the disease under unfavorable conditionsin more details. When the correct approach to the interpretation of the results of molecular studies, it is possible to identify not only the genes underlying hereditary diseases, but also the genes of predisposition to them [30]. The VDR is located on chromosome 12, contains 60 thousand base pairs, and includes 11 exons [31]. After binding of vitamin D to the receptor, this complex forms dimers with other receptors, more often with the retinoic acid receptor (RXR). In this form, the ligand-bound dimerized receptor binds to a specific region of DNA. With the help of other transcriptional co-activators or repressor co-genes, gene expression is either stimulated or inhibited. Several restriction fragment length polymorphisms (RFLPs) are identified in the VDR gene [32].

The VDR gene is expressed in a variety of tissues, mainly in the intestines, kidneys, parathyroid gland, and bones. All of these tissues and organs are involved into maintaining calcium homeostasis. The VDR transcription factor is a member of the thyroid gland, a superfamily of nuclear steroid receptors [33]. The protein has five functional domains: DNA binding, a signaling domain of nuclear localization (providing protein delivery to the nucleus), a hormone, a dimerization domain (required for heterodimerization with the X-retinoid receptor), and a transactivation domain (interacts with cofactors) [34]. Acting as a transactivator, VDR binds to a ligand, enters the nucleus, forms a homo-or heterodimer with one of the three retinoid X-receptors (RXRa, RXRp, RXRy), binds to vitamin D response elements (DNA regulatory sequences) and transactivates target-genes [33].

Co-morbidities, and in particular the 1,25 (OH) 2 D3-VDR complex, regulate multiple genes. Among them are genes that are responsible for the metabolism of calcium and phosphate, as well as for normal bone mineralization. In the absence of an active form of vitamin D or functional VDR, calcium absorption is impaired and, as a consequence, the level of bone mineralization decreases. Such disorders lead to the development of rickets for children and to osteomalacia for adults [34].

Mutations in the VDR are the source of a rare genetic disease, vitamin D-dependent rickets type 2A [35].

Studies, devoted to identifying the correlation of VDR polymorphism with bone pathology, have confirmed its contribution to the osteoporosis and osteoarthritis development [36]. A study among Pakistani residents demonstrated an association of VDR polymorphisms (rs10735810, rs7975232, rs731236, and rs1544410) with the occurrence of rheumatoid arthritis and osteoarthritis. Similar associations of VDR polymorphisms can be traced in other groups: Egyptian (rs7975232, rs731236, and rs1544410), French (rs10735810), Canadian (rs10735810), and Tunisian (rs10735810) [35].

A number of researchers associate VDR polymorphism with various tumor diseases, however, compared with other oncogenes, the role of VDR is poorly explored [37].

Another gene-candidate for bone disease is the TNFSF11 gene, which encodes the RANKL protein. Their cytokines play a key role in the formation, differentiation and functioning of osteoclasts [38]. Osteoprotegerin (OPG), a soluble member of the TNF family, secreted by preosteoblast / stromal cells. It blocks the RANKL / RANK interaction, acting as a decoy (decoy receptor) for RANKL. In the process of differentiation, RANKL acts as a regulator of bone resorption, while OPG acts as a higher regulator of bone formation due to the fact that for a rather long period the development of osteoclasts is not stimulated [39,40]. Several mutations of the TNFSF11 gene are identified, one of which is the polymorphism rs9594738 (C> T). Today a number of studies aimed at exploring the role of this polymorphism in the formation of pathologies of the skeletal system have been conducted [41,42]. Osteoclasts are large polynuclear cells of a hematopoietic nature that are differentiated from monocytic / macrophage progenitor cells. The fact that the differentiation of osteoclasts requires the presence of bone marrow stromal cells or osteoblasts led to the discovery of two osteoblast-derived factors. These factors are required to trigger osteoclastogenesis: macrophage colony stimulating factor (M-CSF) and ligand (RANKL) receptor of nuclear factor activator (RANK). They interact with two main transcriptional complexes: NFkB (nuclear factor kB) and AP-1 (activator protein 1 of the transcriptional complex) which, in turn, consists of proteins FOS (human oncogene FOS) and JUN (oncogene JUN). These proteins activate signaling cascades that are necessary for the differentiation, functioning and life expectancy of osteoclasts [43]. Factors that control the expression of genes typical for the osteoclast line and are necessary for the process of osteoclast differentiation include PU. 1 (tissue-specific transcription factor 1), MITF (microphthalmia-associated transcription factor), NFATc1 (nuclear factor of activated T cells 1), and transmembrane adapter protein DAP12 [44,45]. Markers of osteoclast maturity, their viability and resorption capacity are: tartrate-resistant acid phosphatase (TRAP), carbonic anhydrase II (Ca II), and cathepsin K (CTSK) [45].Osteoclastogenesis and bone resorption are modulated by a number of growth factors, cytokines and hormones that act both directly on osteoclasts and indirectly through osteoclast stromal cells. Examples of pro-resorptive factors include tumor necrosis factor a, interleukin-1, parathyroid hormone and others, while estrogens, calcitonin, bone morphogenic proteins 2 and 4, calcium, interferons b and g, interleukins-4, -10 act as antiresorptive factors, -17 and -18 [46].

The problem of vitamin D supply among children, adolescents and adults in recent decades has been intensively studied all over the world [47,48]. In various countries and regions of the world large-scale studies are being carried out to analyze the prevalence of vitamin D deficiency, and their impact on health of different population groups , the correlation with the frequency and structure of morbidity types [48,49]. Bone homeostasis is provided by the balance and coordination of bone formation and bone resorption processes, which are the result of the cooperated action of many genes.

Mutations in these genes, as well as the imbalance of their cooperated action, lead to the various forms of skeletal pathology and increase their spectrum in the population. At one end of this spectrum are conditions characterized by decreased bone mass, while at the other - abnormalities characterized by increased bone mass due to predominantly monogenic mutations. These monogenic abnormalities are of particular interest for both: the identification of new genes, involved in bone remodeling, and the study of molecular genetic mechanisms that make it possible to understand how mutational changes in one gene can radically affect the balance between the formation of new and resorption of old bone tissue.

According to the latest clinical guidelines of the Endocrinological Society, 40-60% of the world's population is considered to have insufficient level of vitamin D3 [50].

As mentioned above, vitamin D deficiency among children is manifested by damage to the musculoskeletal system with the development of rickets, osteomalacia. A decrease in vitamin D3 levels already in childhood is associated with a high risk of cardiovascular disease, namely, high blood pressure, a decrease in high density lipoproteins and an increase in the concentration of parathyroid hormone. These changes can lead to the development of cardiovascular diseases at a young age [51]. When correcting the deficiency, it is necessary to take into consideration other

indicators, such as the level of phosphates, parathyroid hormone, renin, and fibroblasts 23 [52].

When it comes to newborns, vitamin D deficiency is becoming a worldwide problem. It has been documented among newborns ranging from 73% in New Zealand [53] to 94% in Jordan [54]. In Africa, vitamin D deficiency and related effects are also not uncommon; for example, in Kenya, the incidence of rickets in prematurity by 6 months of age was 58.8% and was more common in male infants than in female infants [55]. Msomekelaetalconducted a study in Tanzania to assess vitamin D status in newborns of varying birth weights and gestational ages, and to identify associated neonatal and maternal factors. Metabolic bone diseases have been found to be more common in very low birth weight infants who are exclusively breastfed, with nearly 33% of the study population having clinical rickets at 12 weeks [56]. Maternal vitamin D deficiency during pregnancy has been documented in a number of studies. For example, 18% of pregnant women in the UK, 25% in the UAE, 80% in Iran, 42% in northern India, 61% in New Zealand have a concentration of 25 (OH) D <25 nmol / L. These studies cause caution, because children enter the world already with a deficiency of vitamin D, which begins in the womb. These fears are based on the close connection between mother and fetus [57]. Vitamin D levels in many countries are critically low in mother-child couples at birth. Even babies born by mothers with an excess of vitamin D begin to experience vitamin D deficiency after 8 weeks if the diet is not supplemented with this vitamin. Particular attention is paid to vitamin D deficiency during pregnancy because in this case the fetus develops in a condition of vitamin D hypovitaminosis, which probably has a significant effect on innate immunity and the development of bone tissue in the fetus. Vitamin D deficiency during pregnancy may not only worsen the condition of the mother's skeletal system and the formation of the fetal skeleton, but also has a certain effect on chronic susceptibility to diseases soon after birth, as well as at a later age [58]. Low vitamin D levels in the perinatal and neonatal period may also increase susceptibility to schizophrenia, diabetes mellitus type 1, and multiple sclerosis later in life. Vitamin D deficiency during pregnancy can affect the fetus through specific target organ effects or through epigenetic modifications, including the immune system, which can lead to increased susceptibility to infectious diseases soon after birth and later in life [59].

As a result, the general understanding of the role of genetic factors in the pathogenesis of vitamin D deficiency is compelling, but there are still enough questions regarding the contribution of specific genes that regulate the growth and development of the skeletal system. The polymorphism of the vitamin D gene in children of different ages in Kazakhstan has been insufficiently studied. There are isolated works on this problem among adolescent children [60].

The search for genetic markers of molecules that affect the onset and course of vitamin D deficiency is of theoretical and practical interest in pediatrics, therapy, and gerontology.

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