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

Abstract

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 x 10(-4) and P(tdt)=2.4 x 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 x 10(-3), and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1 x 10(-3). The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17beta-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 approximately 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.

Interleukin-6 and Diabetes

“…Thus, the observation in the Danish type 1 diabetes families is favored as the most reliable (Table 1). We found highly significant linkage and association in females exclusively, with IL6-174C transmission rates of 63 and 66%, respectively (8). Sex-stratified analysis was not investigated (or at least not reported) in the U.K. and Dutch studies (Table 1).…”

“…The human interleukin-6 gene (IL6, Online Mendelian Inheri-tance in Man #147620) maps to chromosome 7p21. IL6 has a high degree of sequence homology with the murine Il6, in particular, in regulatory proximal promoter sequences (8).…”

“…We (8) and others (15,16) have evaluated the association of the IL6-174GϾC SNP with type 1 diabetes with widely differing results ( Table 1). Because all family-based studies (despite significant power) failed to confirm the initial observation of association in the U.K. case-control cohort (15), this association is most likely "spurious" ( Table 1).…”

“…In families with one IL6-174CC homozygous and one IL6-174GC heterozygous parent, a striking effect of the transmitted allele from the heterozygous parent was observed in female offspring in that IL6-174C and IL6-174G conferred risk and protection, respectively (8).…”

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

“…Estos resultados podrían relacionarse a las diferencias hormonales producidas durante la pubertad entre ambos sexos 7 . Finalmente, también se ha demostrado que los polimorfi smos -174G›C y -597 G›A en el gen promotor de la IL-6 estarían asociados con hiperandrogenismo en mujeres sin diabetes mellitus y que la presencia del alelo G se asociaría con elevados niveles de IL-6, cortisol basal, 11 deoxicortisol, 17 hidroxiprogesterona y testosterona 17 .…”