ABSTRACT
Background: Type I diabetes mellitus (T1DM) is a significant health challenge, especially for children, owing to its chronic autoimmune nature. Although the exact etiology of T1DM remains elusive, the interplay of genetic predisposition, immune responses, and environmental factors are postulated. Genetic factors control immune reactivity against ß-cells. Given the pivotal roles of CIITA and CLEC2D genes in modulating a variety of immune pathologies, we hypothesized that genetic variations in CIITA and CLEC2D genes may impact T1DM disease predisposition. This study was designed to explore the association between gene polymorphisms in CIITA (rs8048002) and CLEC2D (rs2114870) and type 1 diabetes (T1DM), with a focus on analyzing the functional consequence of those gene variants. Methods: The study enlisted 178 healthy controls and 148 individuals with type 1 diabetes (T1DM) from Suez Canal University Hospital. Genotyping for CIITA and CLEC2D was done using allelic-discrimination polymerase chain reaction (PCR). Levels of glycated hemoglobin (HbA1c) and lipid profiles were determined through automated analyzer, while fasting blood glucose and insulin serum levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. RegulomeDB was used to examine the regulatory functions of CIITA (rs8048002) and CLEC2D (rs2114870) gene variants. Results: Analysis of the genotype distribution of the CIITA rs8048002 polymorphism revealed a significantly higher prevalence of the rare C allele in T1DM patients compared to the control group (OR = 1.77; P = 0.001). Both the CIITA rs8048002 heterozygote TC genotype (OR = 1.93; P = 0.005) and the rare homozygote CC genotype (OR = 3.62; P = 0.006) were significantly more frequent in children with T1DM when compared to the control group. Conversely, the rare A allele of CLEC2D rs2114870 was found to be significantly less frequent in T1DM children relative to the control group (OR = 0.58; P = 0.002). The heterozygote GA genotype (OR = 0.61; P = 0.033) and the rare homozygote AA genotype (OR = 0.25; P = 0.004) were also significantly less frequent in T1DM patients compared to the control group. Both CIITA (rs8048002) and CLEC2D (rs2114870) gene variants were predicted to have regulatory functions, indicated by a RegulomeDB score of (1f) for each. Conclusion: The rare C allele of CIITA rs8048002 genetic variant was associated with an increased risk of developing T1DM, while the less common A allele of CLEC2D rs2114870 was associated with a reduced risk of T1DM. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-024-01402-w.
ABSTRACT
Background: Bare lymphocyte syndrome type II (BLS II) is a rare form of severe combined immunodeficiency caused by mutations in the CIITA gene, which regulates major histocompatibility complex class II (MHC II) expression. Objective: We report the case of a Saudi boy with a novel mutation in the CIITA gene who presented with acute and late meningoencephalomyelitis, resulting in severe neurodevelopmental regression. Methods: We reviewed the patient's clinical and laboratory data obtained from medical records and performed a literature search on BLS II. Results: The patient presented with acute meningoencephalomyelitis confirmed by MRI findings and was later found to carry a homozygous pathogenic variant in the CIITA gene p.(Leu473Hisfs*15). The patient had no MCH II expression, confirming the genetic diagnosis of autosomal recessive BLS II. Surprisingly, the patient's prior clinical history was unremarkable for significant infections or autoimmunity. Conclusions: We report a case with a novel CIITA gene mutation presenting atypically with a late and isolated severe infection. Isolated severe meningoencephalomyelitis may be a manifestation of primary immunodeficiency.
ABSTRACT
The objective of this study was to investigate the association between the HLA alleles at the DQA1, DQB1 and DRB1 loci, the CIITA genetic polymorphisms -168A/G and +1614G/C, and susceptibility to multiple sclerosis (MS) in a sample from Rio de Janeiro State, Brazil. Furthermore, we wished to determine whether any of these associations might be more significant in women compared with men. DNA samples from 52 relapsing-remitting MS (RRMS) patients and 126 healthy controls matched for sex and age were analyzed. We identified a significant HLA-DRB1*15:01-MS association that was female-specific (Odds Ratio (OR) = 4.78; p = 0.001). Furthermore, we observed that the +1614G/C mutation in combination with the HLA-DRB1*15:01 allele increased susceptibility to MS in females (OR = 4.55; p = 0.01). Together, these findings highlight the polygenic nature of MS.
O objetivo deste estudo foi investigar a associação entre alelos HLA, loci DQA1, DQB1 e DRB1, polimorfismos -168A/G e +1614G/C no gene CIITA, e suscetibilidade à esclerose múltipla (EM) em uma amostra de Rio de Janeiro, Brasil. Além disso, buscou-se determinar se alguma dessas associações pode ser gênero-dependente. Foram analisadas amostras de DNA de 52 pacientes com EM reincidente-remitente (EMRR) e 126 controles saudáveis pareados por sexo e idade. Foi identificada associação significativa HLA-DRB1*15:01-EMRR, que foi específica para o gênero feminino (Odds Ratio (OR) = 4,78, p = 0,001). Além disso, observou-se que o polimorfismo +1614 G/C, em combinação com o alelo HLA-DRB1*15:01 provoca o aumento da susceptibilidade à EM em pacientes do sexo feminino (OR = 4,55, p = 0,01). Juntos, estes resultados destacam a natureza poligênica da EM.
