CD226 rs763361 is associated with the susceptibility to type 1 diabetes and greater frequency of GAD65 autoantibody in a Brazilian cohort.

CD226 rs763361 variant increases susceptibility to type 1 diabetes (T1D) in Caucasians. There is no data about CD226 variants in the very heterogeneous Brazilian population bearing a wide degree of admixture. We investigated its association with T1D susceptibility, clinical phenotypes, and autoimmune manifestations (islet and extrapancreatic autoantibodies). Casuistry. 532 T1D patients and 594 controls in a case-control study. Initially, CD226 coding regions and boundaries were sequenced in a subset of 106 T1D patients and 102 controls. In a second step, two CD226 variants, rs763361 (exon 7) and rs727088 (3' UTR region), involved with CD226 regulation, were genotyped in the entire cohort. C-peptide and autoantibody levels were determined. No new polymorphic variant was found. The variants rs763361 and rs727088 were in strong linkage disequilibrium. The TT genotype of rs763361 was associated with TID risk (OR = 1.503; 95% CI = 1.135-1.991; P = 0.0044), mainly in females (P = 0.0012), greater frequency of anti-GAD autoantibody (31.9% × 24.5%; OR = 1.57; CI = 1.136-2.194; P = 0.0081), and lower C-peptide levels when compared to those with TC + CC genotypes (0.41 ± 0.30 ng/dL versus 0.70 ± 0.53 ng/dL P = 0.0218). Conclusions. The rs763361 variant of CD226 gene (TT genotype) was associated with susceptibility to T1D and with the degree of aggressiveness of the disease in T1D patients from Brazil. Ancestry had no effect.

Variantes do gene CD226 associadas com a susceptibilidade ao diabetes mellitus tipo 1 autoimune / CD226 gene variants associated with susceptibility to type 1, immune mediated, diabetes

Recentemente, estudos de Genome Wide Association (GWA) identificaram uma nova região cromossômica, 18q22, como de susceptibilidade ao Diabetes tipo 1 autoimune (DM1A). Nesta região localiza-se o gene CD226, responsável por codificar uma molécula de adesão leucocitária (CD226) envolvida no processo de adesão celular, diferenciação de células T CD4+ virgens, citotoxicidade induzida por células natural killer (NK) e produção de citocinas. Até o momento, apenas o polimorfismo rs763361 A/G foi relacionado ao diabetes autoimune e pouco é conhecido quanto ao envolvimento de outras variantes do CD226, associadas a outras doenças autoimunes, na patogênese do DM1A. Com o objetivo de definir as variantes polimórficas relacionadas à susceptibilidade ao DM1A, às suas características fenotípicas e outras manifestações de autoimunidade, 532 pacientes diabéticos tipo 1A e 594 controles normais foram envolvidos neste estudo. Inicialmente, em um subgrupo de 106 diabéticos e 102 controles, as regiões codificadoras e flanqueadoras do gene CD226, obtidas do DNA genômico de leucócitos do sangue periférico, foram amplificadas pela técnica de Reação em Cadeia da Polimerase e submetidas à sequenciamento direto. Em uma segunda etapa, os polimorfismos rs763361, rs1788101 e rs727088 foram genotipados pelo ensaio TaqMan nos demais pacientes e controles. Resultados: foram identificadas 12 variantes no gene CD226, sete com frequência acima de 5%. Nenhuma variante nova foi encontrada. A variante rs727088 não estava em equilíbrio de Hardy Weinberg no grupo controle. Os genótipos AA da variante rs763361 e CC do rs727088 foram associados ao risco de DM1A e estavam em desequilíbrio de ligação. O genótipo do haplótipo ACAC, formado pelas variantes de risco, predominou nos pacientes diabéticos. Tanto o genótipo AA do rs763361 como o CC do rs727088 e o genótipo do haplótipo ACAC foram associados com menores valores de peptídeo C em pacientes com até dois anos de duração da doença. Nenhum...

Recently, Genome Wide Association (GWA) studies identified a new locus, 18q22, as a canditate to Type 1 A, or immune mediated diabetes (T1AD) susceptibility. This locus harbors the CD226 gene, responsible for encoding the leukocyte adhesion molecule (CD226) involved in cell adhesion, differentiation of naïve CD4+T cells, cytotoxicity induced by natural killer (NK) cells and cytokine production. Although just one single nucleotide polymorphism (SNP) rs763361 A/G had been related to T1AD, little is known about the involvement of new variants of CD226, implicated in other autoimmune disorders, in the pathogenesis of T1AD. In order to identify polymorphic variants related to T1AD susceptibility and their influences in phenotypic characteristics and other manifestations of autoimmunity, 532 type 1A diabetic patients and 594 health controls were enrolled in this study. Initially, in a subset of 106 diabetics and 102 controls, coding and flanking regions of CD226 gene obtained from genomic DNA extraction were amplified by polymerase chain reaction technique and subjected to direct sequencing. In a second step, the polymorphisms rs763361, rs727088 and rs1788101 were genotyped by TaqMan assay in the remaining patients and controls. Results: 12 variants in CD226 gene, seven of them with frequency above 5 % where identified. We did not found new variants. The variant rs727088 was not in Hardy Weinberg equilibrium in the control group. The genotypes AA (OR=1.45; p=0.005) and CC (OR=1.41; p=0.01) related to rs763361 and rs727088 variants respectively, were associated with risk of T1AD. Both predominated in female (p<0.01). Further, these variants were in linkage disequilibrium. The genotype haplotype ACAC formed by the risk variants was more frequent in patients with diabetes (30.5% x 25.6%; OR=1.42; p=0.014). The AA genotype of rs763361, the CC genotype and ACAC genotype haplotype were associated with lower levels of C-peptide in patients with no more than two...

Unregulated IL-23/IL-17 immune response in autoimmune diseases.

INTRODUCTION: Type 1A diabetes (T1D) is an autoimmune disease resulting from the selective destruction of pancreatic beta cells by T cells most likely due to interaction of environmental and genetic factors. The CD4(+) T cells, largely implicated in this disease, comprise different subsets; based on the cytokines they produce. These subsets include Th1, Th2, regulatory T cells and another population of recently described T cells called Th17 cells. Increased expression of interleukin 17 (IL-17) has been detected in sera and in target tissues of patients with various autoimmune diseases. The differentiation of Th17 cells from naïve T cells appears to involve signals from TGF-beta, IL-6, IL-21, IL-1beta and IL-23. IL-23, a member of the IL-12 family, which activate the effector function of Th17 cells to promote inflammatory responses. In animal models, IL-23 is involved in the development of autoimmune diabetes. In humans, it seems to cause multi-organ inflammation, contributing to rheumatoid arthritis, inflammatory bowel disease and celiac disease manifestations. CONCLUSIONS: The discovery that certain autoimmune disorders might be largely mediated by an unregulated IL-23/IL-17 response has important implications for the development of novel therapies for these diseases.