Concentrações séricas e variantes de genes relacionados ao metabolismo da vitamina D em crianças e adolescentes: associação com estado inflamatório da Artrite Idiopática Juvenil
Data
2023-08-24
Autores
Rodrigues, Wellington Douglas Rocha 
Orientadores
Terreri, Maria Teresa de Sande e Lemos Ramos Ascensão
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A Artrite Idiopática Juvenil (AIJ) é considerada a doença reumática crônica
mais comum na faixa etária pediátrica. Estudos têm demonstrado que a deficiência de
vitamina D está associada a um perfil mais inflamatório e maior atividade da doença.
Assim, variantes de nucleotídeo único (SNVs) do gene VDR (receptor de vitamina D) e
de genes associados ao metabolismo da vitamina D surgiram como candidatos à
suscetibilidade a doenças autoimunes. Objetivos: Avaliar as concentrações de vitamina
D (25(OH)D), a frequência das variantes rs7041:A>C e rs4588:G>T do gene GC;
rs10500804:T>G, rs10741657:G>A e rs1562902:C>T do gene CYP2R1;
rs3829251:G>A do gene DHCR7; e rs7975232:C>A (Apal), rs2228570:A>G (FokI) e
rs731236:A>G (TaqI) do gene VDR, bem como a possível associação destas variantes
com as concentrações séricas de 25(OH)D e as interleucinas IL 1β, IL 6, IL 23 e TNF
alfa em crianças e adolescentes com AIJ e seus subtipos. Métodos: Estudo transversal,
prospectivo, que incluiu 117 crianças e adolescentes com diagnóstico de AIJ. A
genotipagem das variantes foi realizada por reação em cadeia da polimerase (PCR) em
tempo real, usando a metodologia TaqMan. A concentração sérica de 25(OH)D foi
determinada por eletroquimioluminescência e a quantificação sérica das interleucinas foi
realizada por meio da técnica Multiple Analytic Profile (xMAP). Resultados: A
concentração mediana de 25(OH)D foi de 27,9 [23,5 33,8] ng/mL. Deficiência e
insuficiência de vitamina D foram observadas em 10,9% e 48,7%, respectivamente.
Todas as variantes estudadas estavam em equilíbrio de Hardy Weinberg, exceto a
variante rs7041:A>C do gene GC. As comparações da frequência dos genótipos e alelos
não foi diferente de acordo com a atividade da doença e os subtipos de AIJ. Também não
foi observada diferença nas concentrações de 25(OH)D de acordo com os genótipos das
variantes. Considerando a concentração das interleucinas de acordo com os genótipos
das variantes estudadas, a dosagem de IL 1β foi significantemente menor nos portadores
do genótipo GG da variante FokI (rs2228570:A>G) do gene VDR em relação aos
portadores do genótipo AA (1,52±2,25 pg/mL versus 7,02±22,57 pg/mL, p=0,028), o
mesmo foi observado para os portadores do alelo G em relação ao alelo A no modelo
recessivo (1,5±1,87 pg/mL versus 7,02±22,57 pg/mL, p=0,032). Os portadores do alelo
A da variante rs7041:A>C do gene GC apresentaram maiores valores de IL 23 em relação
aos portadores do alelo C no modelo dominante (448,73±423,69 pg/mL versus
280,68±234,5 pg/mL, p=0,013).
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Conclusões: 59,6% dos participantes apresentaram deficiência ou insuficiência de
vitamina D. Todas as variantes estudadas estavam em equilíbrio de Hardy Weinberg,
exceto a variante rs7041:A>C do gene GC. Não foi observada diferença na frequência
dos alelos ou genótipos das variantes estudadas e o subtipo de AIJ. As frequências dos
genótipos e alelos não foi diferente de acordo com a concentração de 25(OH)D. Os
portadores do alelo G da variante VDR:rs2228570 apresentaram concentrações de IL 1β
significantemente menores. Os portadores do alelo A da variante GC:rs7041
apresentaram maiores valores de IL 23
Introduction: Juvenile Idiopathic Arthritis (JIA) is considered the most common chronic rheumatic disease in the pediatric age group. Studies have shown that vitamin D deficiency is associated with a more inflammatory profile and greater disease activity. Thus, single nucleotide variants (SNVs) of the VDR gene (vitamin D receptor) and genes associated with vitamin D metabolism have emerged as candidates for susceptibility to autoimmune diseases. Objectives: To evaluate the levels of vitamin D (25(OH)D), the frequency of the rs7041:A>C and rs4588:G>T variants of the GC gene; rs10500804:T>G, rs10741657:G>A and rs1562902:C>T of the CYP2R1 gene; rs3829251:G>A of the DHCR7 gene; and rs7975232:C>A (Apal), rs2228570:A>G (FokI) and rs731236:A>G (TaqI) of the VDR gene, as well as the possible association of these variants with 25(OH)D serum concentrations and interleukins IL1, IL6, IL23 and TNFalpha in children and adolescents with JIA and its subtypes. Methods: Crosssectional, prospective study that included 117 children and adolescents diagnosed with JIA. Genotyping of variants was performed by realtime polymerase chain reaction (PCR) using the TaqMan methodology. The serum concentration of 25(OH)D was determined by electrochemiluminescence and the serum quantification of interleukins was performed using the Multiple Analytic Profile (xMAP) technique. Results: The median level of 25(OH)D was 27.9 [23.533.8] ng/mL. Vitamin D deficiency and insufficiency were observed in 10.9% and 48.7%, respectively. Comparisons of genotype and allele frequency did not differ according to disease activity and JIA subtypes. Also, no difference was observed in the concentrations of 25(OH)D according to the genotypes of the variants. Considering the levels of interleukins according to the genotypes of the variants studied, the IL1β dosage was significantly lower in carriers of the GG genotype of the FokI variant (rs2228570:A>G) of the VDR gene compared to carriers of the AA genotype (1 .52±2.25 pg/mL versus 7.02±22.57 pg/mL, p=0.028), the same was observed for carriers of the G allele in relation to the A allele in the recessive model (1.5±1.87 pg/ml versus 7.02±22.57 pg/ml, p=0.032). Carriers of the A allele of the rs7041:A>C variant of the GC gene had higher IL23 values than those carrying the C allele in the dominant model (448.73±423.69 pg/mL versus 280.68±234,5 pg/ml, p=0.013). Conclusions: 59.6% of participants had vitamin D deficiency or insufficiency. No difference was observed in the frequency of alleles or genotypes of the variants studied and the subtype of JIA. The frequencies of genotypes and alleles did not differ according to 25(OH)D levels. Carriers of the G allele of the VDR:rs2228570 variant had a significantly lower IL1β dosage. Carriers of the A allele of the GC:rs7041 variant had higher IL23 values.
Introduction: Juvenile Idiopathic Arthritis (JIA) is considered the most common chronic rheumatic disease in the pediatric age group. Studies have shown that vitamin D deficiency is associated with a more inflammatory profile and greater disease activity. Thus, single nucleotide variants (SNVs) of the VDR gene (vitamin D receptor) and genes associated with vitamin D metabolism have emerged as candidates for susceptibility to autoimmune diseases. Objectives: To evaluate the levels of vitamin D (25(OH)D), the frequency of the rs7041:A>C and rs4588:G>T variants of the GC gene; rs10500804:T>G, rs10741657:G>A and rs1562902:C>T of the CYP2R1 gene; rs3829251:G>A of the DHCR7 gene; and rs7975232:C>A (Apal), rs2228570:A>G (FokI) and rs731236:A>G (TaqI) of the VDR gene, as well as the possible association of these variants with 25(OH)D serum concentrations and interleukins IL1, IL6, IL23 and TNFalpha in children and adolescents with JIA and its subtypes. Methods: Crosssectional, prospective study that included 117 children and adolescents diagnosed with JIA. Genotyping of variants was performed by realtime polymerase chain reaction (PCR) using the TaqMan methodology. The serum concentration of 25(OH)D was determined by electrochemiluminescence and the serum quantification of interleukins was performed using the Multiple Analytic Profile (xMAP) technique. Results: The median level of 25(OH)D was 27.9 [23.533.8] ng/mL. Vitamin D deficiency and insufficiency were observed in 10.9% and 48.7%, respectively. Comparisons of genotype and allele frequency did not differ according to disease activity and JIA subtypes. Also, no difference was observed in the concentrations of 25(OH)D according to the genotypes of the variants. Considering the levels of interleukins according to the genotypes of the variants studied, the IL1β dosage was significantly lower in carriers of the GG genotype of the FokI variant (rs2228570:A>G) of the VDR gene compared to carriers of the AA genotype (1 .52±2.25 pg/mL versus 7.02±22.57 pg/mL, p=0.028), the same was observed for carriers of the G allele in relation to the A allele in the recessive model (1.5±1.87 pg/ml versus 7.02±22.57 pg/ml, p=0.032). Carriers of the A allele of the rs7041:A>C variant of the GC gene had higher IL23 values than those carrying the C allele in the dominant model (448.73±423.69 pg/mL versus 280.68±234,5 pg/ml, p=0.013). Conclusions: 59.6% of participants had vitamin D deficiency or insufficiency. No difference was observed in the frequency of alleles or genotypes of the variants studied and the subtype of JIA. The frequencies of genotypes and alleles did not differ according to 25(OH)D levels. Carriers of the G allele of the VDR:rs2228570 variant had a significantly lower IL1β dosage. Carriers of the A allele of the GC:rs7041 variant had higher IL23 values.