Association of a functional 17β-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females

The type 1 diabetes mellitus (T1DM) candidate gene SNP IL6-174G/C was genotyped in 253 Danish T1DM families (1129 individuals). TDT analysis demonstrated linkage in the presence of association between the IL6-174C allele and T1DM in the 416 T1DM offspring, Ptdt=0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively; Ptdt=6.5×10−4 and Ptdt=2.4×10−4, respectively. Random transmission of the IL6-174C/G alleles was found in T1DM males, non-T1DM males and non-T1DM females; all Ptdt≥0.37. Heterogeneity analyses (T1DM versus non-T1DM females) excluded preferential meiotic segregation in females, P=4.6×10−3, and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1×10−3. The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17β-estradiol (E2) on the IL6-174G/C variants was investigated by reporter studies. The PMA stimulated activity of the T1DM risk IL6-174C variant exceeded that of the T1DM protective IL6-174G variant by ∼70% in the absence of E2 (Pc=0.004), but not with E2 present (Pc=0.12). The PMA stimulated activity of the IL6-174G variant was repressed without E2 present, but was derepressed by addition of E2, Pc=0.024. In contrast, the PMA stimulated IL6-174C activity was unaffected by E2 as were the constitutive activities of the IL6-174G/C variants. In conclusion, higher IL6 promoter activity may confer risk to T1DM in very young females. This excess risk is negated with increasing age, possibly by the increasing E2 levels in puberty.