RESUMO
Background: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease characterized by destructive and inflammatory damage to the joints. The aim in this study was to compare vitamin D levels between children and adolescents, 1-18 years of age, with juvenile idiopathic arthritis (JIA) and a health control group of peers. We considered effects of endogenous, exogenous, and genetic factors on measured differences in vitamin D levels among children with JIA. Methods: Our findings are based on a study sample of 150 patients with various variants of JIA and 277 healthy children. The blood level of vitamin D was assessed by calcidiol level. The following factors were included in our analysis: age and sex; level of insolation in three regions of country (center, south, north); assessment of dietary intake of vitamin D; effect of prophylactic doses of cholecalciferol; a relationship between the TaqI, FokI, and BsmI polymorphisms of the VDR gene and serum 25(OH)D concentration. Results: We identified a high frequency of low vitamin D among children with JIA, prevalence of 66%, with the medial level of vitamin D being within the range of "insufficient" vitamin D. We also show that the dietary intake of vitamin D by children with JIA is well below expected norms, and that prophylactic doses of vitamin D supplementation (cholecalciferol) at a dose of 500-1,000 IU/day and 1,500-2,000 IU/day do not meet the vitamin D needs of children with JIA. Of importance, we show that vitamin D levels among children with JIA are not affected by clinical therapies to manage the disease nor by the present of VDR genetic variants. Conclusion: Prophylactic administration of cholecalciferol and season of year play a determining role in the development of vitamin D deficiency and insufficiency.
RESUMO
Background: The problem of vitamin D deficiency is particularly relevant for the entire territory of Russia, since most parts of the country are located above the 42nd geographical latitude and the residents are therefore at risk of vitamin D deficiency. Despite the urgency of the problem, a comprehensive study of the molecular and genetic mechanisms and exogenous factors of vitamin D deficiency in children living in various geographical areas of the Russian Federation has not been conducted. Different variants in the loci of the genes responsible for the synthesis, hydroxylation, and transport of vitamin D (such as DHCR7, CYP2R1, CYP24A1, and GC), as well as VDR gene polymorphisms may also be associated with the risk of vitamin D deficiency. The aim of this study was to analyze the influence of exogenous factors on the blood levels of 25-hydroxyvitamin D (25(OH)D) in children of three regions of the Russian Federation, as well as the relationship of blood 25(OH)D levels with polymorphic variants of cytochrome P450 genes and VDR gene. Methods: We conducted blood 25(OH)D level analysis in 333 healthy children and adolescents in three regions located in different geographical zones of the Russian Federation. We studied the polymorphic variants c.1075A>C (I359L, rs1057910, CYP2C9 * 3) and c.430C>T (R144C, rs1799853, CYP2C9 * 2) in the CYP2C9 gene, c.1334T>C (M445T, rs4986910, CYP3A4 * 3), and CYP3A4 * 1B (c.-392C>T, rs2740574) in the CYP3A4 gene, 1846G>A, (rs3892097, CYP2D6 * 4) in the CYP2D6gene, TaqI (NM_000376.2: c.1056T>C; rs731236), FokI (NM_000376.2:c.2T>C; (rs2228570), and BsmI (NM_000376.2: c.1024+283G>A; rs1544410) in the VDR gene. We also analyzed the influence of exogenous factors on the level of 25(OH)D in children of the three study regions, as well as the relationship of the level of 25(OH)D with variants CYP2C9 * 2 (c.430C>T; R144C), CYP2C9 * 3 (c,1075A>C; I359L), CYP2D6 * 4 (1846G>A), CYP3A4 * 3 (c.1334T>C), and CYP3A4 * 1B (c.-392C>T) and rs731236, rs2228570 and rs1544410 in the VDR gene. Results: We found that the blood level of 25(OH)D depended on the geographical location and the number of sunny days per year. The average blood level of 25(OH)D in adolescent boys was statistically significantly lower than in girls of this age group. The level of 25(OH)D also significantly depended on the prophylactic dose of cholecalciferol administered to the subjects. In the study, it was shown that a dose of cholecalciferol ≥1,000 IU per day can achieve a normal level of 25(OH)D in healthy children. We found no statistically significant association between single-nucleotide polymorphic variants of cytochrome P450 genes (CYP2C9 * 3, CYP3A4 * 3, CYP2C9 * 2, CYP2D6 * 4, and CYP3A4 * 1B) and blood level of 25(OH)D in the subjects. We also did not find a relationship between the TaqI, FokI, and BsmI polymorphisms of the VDR gene and serum 25(OH)D concentration. Conclusion: Exogenous factors (time of year, place of residence, and prophylactic administration of cholecalciferol), as well as endogenous factors (age and sex), play a determining role in the development of vitamin D deficiency and insufficiency; in contrast to genetic factors-polymorphic variants of the genes of xenobiotic phase 1 enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and the VDR gene-which do not play such role. This study shows the need to create a diagnostic algorithm for Vitamin D deficiency based on the age, season of the year, and prophylactic dose of cholecalciferol.
