The −174GG Interleukin-6 Genotype Is Protective From Retinopathy and Nephropathy in Juvenile Onset Type 1 Diabetes Mellitus

Abstract

ABSTRACT:The aim of our study was to determine an association between the Ϫ174GϾC IL-6 polymorphism (rs1800795) and occurrence of retinopathy and nephropathy in type 1 diabetes mellitus (T1DM) patients. Two hundred ten children/adolescents with longstanding T1DM (16.5 Ϯ 3.8 y; with diabetes duration of 8.4 Ϯ 3.0 y) were enrolled into the study. A group of 170 healthy young (16.9 Ϯ 5.2 y) sex-matched volunteers was qualified as the control. The IL-6 polymorphism was genotyped with the PCR-RFLP method. Serum and urine IL-6 concentrations were measured by the ultra-sensitive ELISA tests. The Ϫ174GG genotype was under represented in the diabetic patients compared with the controls. Patients with this genotype were free from nephropathy and retinopathy. The group of Ϫ174GG carriers was characterized by the highest urine IL-6 concentrations in relation to other genotypes. In the multivariate logistic regression analysis adjusted for age, duration of the disease, age of disease onset, HbA1c, and albumin excretion rate, the Ϫ174GG genotype was the only independent variable that significantly decreased the risk of jointly analyzed retinopathy and nephropathy [OR ϭ 0.65; 95% CI ϭ 0.52-0.82; p ϭ 0.0003]. We propose that the Ϫ174GG patients are protected from late diabetic complications by different IL-6 dependent mechanisms. (Pediatr Res 66: 341-345, 2009)

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

“…In addition, the time since diagnosis might not, also, be a confounding factor within this analysis, because no significant difference was found between the CC and GG+GC carriers. The relationship between the CC genotype and kidney injury was also reported by Mysliwska et al , in which T1DM patients carrying the GG genotype were shown to be protected from late diabetic complications, including nephropathy. Because IL‐6 induces several alterations in the kidney, this polymorphism is thought to contribute to renal impairment in T1DM.…”

“…To the best of our knowledge, the present study is the first to evaluate the association of this polymorphism with T1DM in a group of Brazilian patients. The association between T1DM and the C allele and CC genotype for IL6 ‐174G>C was also shown in Polish , British , and Danish patients. In contrast, another British study found that the GG genotype was more frequent in T1DM patients compared with control subjects , and no association was identified in a meta‐analysis including mainly Caucasian patients .…”

“…It has also been suggested that IL‐6 promotes mesangial cell proliferation and increases glomerular endothelial cell permeability, as well as fibronectin expression . IL6 polymorphism ‐174G>C has been associated with T1DM and diabetic complications, such as nephropathy . Another IL6 polymorphism, ‐634C>G, has also been associated with DN .…”

Epidemiology, risk factors and management of paediatric diabetic retinopathy: Table 1

“…A link to elevated DR risk has also been reported for concomitant polymorphisms in genes for enzymes involved in folate metabolism 84. Conversely, a polymorphism in the gene for interleukin 6 in adolescents with type 1 diabetes has been found to have a protective effect 85. Further studies will likely permit a better delineation of the metabolic pathways related, either positively or negatively, to DR development in paediatric populations with diabetes.…”

Research Article Polymorphisms rs1800795 of interleukin-6 and rs2228145 of interleukin-6 receptor genes in Euro-Brazilians with adult-onset type 1 diabetes mellitus

“…Similarly, Tsiavou et al (2004) did not find an association of IL-6 -174G>C (rs1800795) with LADA (Latent Autoimmune Diabetes of the Adult). Additionally, some studies suggest that the -174GG genotype is protective against early T1D onset; however, this protection may be lost later in life (Jahromi et al, 2000;Gillespie et al, 2005;Hermann et al, 2005;Mysliwska et al, 2009).…”