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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,  P  tdt =0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively;  P  tdt =6.5×10 −4  and  P  tdt =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  P  tdt ≥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 (E 2 ) 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 E 2  ( P  c =0.004), but not with E 2  present ( P  c =0.12). The PMA stimulated activity of the  IL6-174G  variant was repressed without E 2  present, but was derepressed by addition of E 2 ,  P  c =0.024. In contrast, the PMA stimulated  IL6-174C  activity was unaffected by E 2  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 E 2  levels in puberty.

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