Is Puberty an Accelerator of Type 1 Diabetes in IL6-174CC Females?

Abstract

The pubertal peak in onset of type 1 diabetes occurs earlier in girls than boys. We postulated that this sex difference might be mediated in part by estrogen or by genes regulated by estrogen, such as the interleukin-6 (IL6) gene. Previous studies concerning the role of an estrogen-sensitive single nucleotide polymorphism (SNP) in the IL6 promoter in type 1 diabetes have proved contradictory. We therefore selected a large, genetically homogenous population-based cohort, analyzed by age at onset and sex, to test the hypothesis that the IL6-174G>C SNP affects age at onset of type 1 diabetes in females but not in males. We found that the IL6-174CC genotype was significantly less frequent in females diagnosed after than in those diagnosed before the age of 10 years (19 vs. 13%, P ‫؍‬ 0.016). No genotype difference was observed in males stratified for age at onset. Among children diagnosed after age 10, the median age of onset was 11.9 years (intraquartile range 10.7-14.6) in 34 girls homozygous for IL6-174C compared with 13.2 years (11.6 -15.4) in 229 girls with other genotypes and 13.5 years (12.0 -15.6) in 339 males with any IL6-174 genotype (P ‫؍‬ 0.012). These data support the hypothesis that pubertal changes may contribute to accelerated onset of type 1 diabetes in genetically susceptible females. This phenomenon may be orchestrated by the action of estrogen on the IL6 promoter.

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

“…Such a genotype distribution profile is in agreement with the data of Gillespie et al (22) who found that the Ϫ174G allele decreases the risk of diabetes type 1 onset before the age of 10 y in girls. An analogous conclusion is derived from the article of Hermann et al (23) who found that the Ϫ174G allele carrier status is associated with a later onset of diabetes type 1 in children.…”

“…Although we did not replicate an association between the Ϫ174GG genotype and a later onset of the disease, which was done by Gillespie et al (22) and Hermann et al (23), we suggest a protective effect of the Ϫ174GG genotype against late diabetic complications in juvenile diabetes. However, one has to treat our results with reservation because they lack the sufficient statistical power (value of power 0.634 with ␣ ϭ 0.05), and to make them reliable, the number of Ϫ174GG patients should be increased about three times.…”

“…In a genome-wide association study comprising 7758 cases and 8852 controls, a borderline significance has been reported for the Ϫ174CC genotype indicating an increased susceptibility to T1DM (21). The three other articles dealing with juvenile onset of T1DM imply that the IL-6 genotypic variants may influence the time of disease onset or modulate the risk of diabetes development (22)(23)(24). Moreover, a recently published article has observed a trend toward higher frequency of retinopathy within the Ϫ174CC genotype in adult diabetes type 1 and type 2 patients (25).…”

Interleukin-6 and Diabetes

“…Studies have independently demonstrated that IL6-174CC females have younger age at onset than females with the IL6-174G allele and all males studied (8,17).…”

Polimorfismo -174 G/C del gen promotor de interleuquina 6 en mujeres con diabetes mellitus tipo 1

“…Jahromi y cols, el año 2000 15 , sugieren que este polimorfi smo estaría asociado con una mayor susceptibilidad al desarrollo de DM1, describiéndose al genotipo homocigoto G/G como altamente asociado a la enfermedad. Durante el año 2005, Gillespie y cols 16 , demuestran que este polimorfi smo se asociaba con la edad de debut en mujeres con DM1, efecto no observado en hombres. Estos resultados podrían relacionarse a las diferencias hormonales producidas durante la pubertad entre ambos sexos 7 .…”