The association between the HLA-G 14-bp insertion/deletion polymorphism and type 1 diabetes

Type 1 diabetes (T1D) is a multifactorial disease that has a strong genetic component. The HLA-G is a nonclassical HLA class I locus that is associated with immunomodulatory functions, including downregulation of innate and adaptive immune responses and induction of immune tolerance. However, there is currently limited information about the involvement of HLA-G in T1D susceptibility. This case-control study aims to investigate the T1D susceptibility association of alleles and genotypes of a widely investigated 14-bp insertion/deletion polymorphism in the HLA-G and to provide further evidence of the frequency distribution of class II HLA-DR-DQ-risk genotypes in T1D children and adolescents in the Brazilian population. The deletion allele and the homozygous deletion genotype are associated with susceptibility to T1D and the insertion allele and the heterozygous deletion/insertion genotype are associated with protection from T1D. We also confirm that genetic susceptibility to T1D is associated with the DRB1*03:01-DQA1*05:01-DQB1*02:01 and DRB1*04-DQA1*03:01-DQB1*03:02 haplotypes in Brazilian northeast region. The DR3-DQ2/DR4-DQ8 genotype conferred the highest detected risk for T1D. Our results identify a novel association of the 14-bp deletion allele and the homozygous deletion genotype with T1D development and provide additional evidence of the importance of HLA class II heterozygous DR3-DQ2/DR4-DQ8 genotype in T1D susceptibility.

Modulation of adhesion molecules by cholesterol-lowering therapy in mononuclear cells from hypercholesterolemic patients

INTRODUCTION:Cholesterol-lowering therapy has been related with several pleiotropic effects including anti-inflammatory action in vascular endothelium; however, their influence on monocyte adhesion molecules is poorly described.AIMS:To investigate the effect of inhibitors of synthesis (statins) and absorption (ezetimibe) of cholesterol on expression of adhesion molecules L-selectin, PSGL-1, VLA-4, LFA-1, and Mac-1 in mononuclear cells in vivo and in vitro using THP-1 cells.METHODS:The influence of simvastatin (10 mg/day), ezetimibe (10 mg/day), and their combination (10 mg each/day) on mRNA expression of adhesion molecules was analyzed in peripheral blood mononuclear cells (PBMC) from hypercholesterolemics. The effects of atorvastatin, simvastatin, and ezetimibe on mRNA and protein expression of adhesion molecules were also evaluated in THP-1 cells.RESULTS:Simvastatin/ezetimibe combination, but not the monotherapies, reduced the mRNA expression of the PSGL-1, LFA-1, and Mac-1 genes in PBMC from hypercholesterolemics. Total and LDL cholesterol in serum correlated with PSGL-1 mRNA expression, whereas HDL cholesterol negatively correlated with mRNA levels of L-selectin and VLA-4 genes (P < 0.05). Plasma hsCRP was also correlated with mRNA levels of VLA-4, LFA-1, and Mac-1 (P < 0.05). Atorvastatin and simvastatin at 10 μM reduced mRNA and protein expression of L-selectin, PSGL-1, and VLA-4 in THP-1 cells (P < 0.05).CONCLUSION:Cholesterol-lowering therapy modulates gene expression of adhesion molecules in PBMC from hypercholesterolemics and THP-1 cells. Simvastatin/ezetimibe combination gives more benefits by reducing to a larger extent the expression of adhesion molecules in mononuclear cells.

Association of polymorphisms in IL6 gene promoter region with type 1 diabetes and increased albumin-to-creatinine ratio

BACKGROUND:Pro-inflammatory cytokines, such as interleukin-6 (IL-6), have been considered as key factors in type 1 diabetes mellitus (T1DM) and diabetic nephropathy, thus, our aim was to investigate the association of IL6-174G>C (rs1800795) and -634C>G (rs1800796) polymorphisms with T1DM susceptibility and diabetic nephropathy.METHODS:These polymorphisms were analyzed in 144 children and adolescents with T1DM and 173 normoglycemic control subjects. Glycemic control, laboratory parameters of kidney function and serum lipids were evaluated. By studying only T1DM patients, we evaluated the polymorphisms associated with relevant biochemical parameters in various genetic models.RESULTS:Type 1 diabetes mellitus patients showed poor glycemic control and albumin-to-creatinine ratio, total cholesterol and LDL-cholesterol levels increased when compared with normoglycemic subjects (p G polymorphism...

Low bone mineral density in Type 1 diabetic patients: influence of reduced IGF1, IGF1R, and TGFB1 expression

BACKGROUND:The negative effect of Type 1 diabetes (T1D) on growth factors of bone metabolism leads to a reduction in bone mineral density (BMD). Therefore, this study aimed to evaluate the association between BMD and IGF1, IGF1R and TGFB1 expression in children and adolescents with T1D. Moreover, the influences of age at diagnosis, time since diagnosis, glycemic control, and albuminuria on BMD were investigated.METHODS:Eighty-six T1D children/adolescents (T1D group) and ninety normoglycemic controls (NG group) were included. T1D patients were analyzed altogether, and divided into two groups according to their glycemic profile (T1D with good glycemic control [T1DG group] and T1D with poor glycemic control [T1DP group]). BMD was assessed by dual energy X-ray absorptiometry. Glycemic control, renal function, and bone markers were also assessed. IGF1, IGF1R, and TGFB1 expressions were measured by real-time PCR.RESULTS:Patients with T1D showed low BMD and poor glycemic control. Serum total calcium and albumin-to-creatinine ratio were higher in the T1DP group compared to the T1DG group (p = 0.003 and p = 0.035, respectively). There was a reduction of IGF1, IGF1R, and TGFB1 expression in the T1D and T1DP groups compared to the NG group (p < 0.05).CONCLUSIONS:The decreased IGF1, IGF1R, and TGFB1 expression in the T1D and T1DP group of patients, who presented with T1D at an early age, had been diagnosed with T1D for a longer time, had poor glycemic control and albuminuria, may contribute to low BMD. This article is protected by copyright. All rights reserved.