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Human Molecular Genetics, 2003, Vol. 12, No. 10 1101-1110
DOI: 10.1093/hmg/ddg132
© 2003 Oxford University Press

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

Ole P. Kristiansen1,{dagger}, Runa L. Nolsøe1,{dagger}, Lykke Larsen1, Anette M.P. Gjesing1, Jesper Johannesen1, Zenia M. Larsen1, Anne E. Lykkesfeldt2, Allan E. Karlsen1, Flemming Pociot1, Thomas Mandrup-Poulsen1,3,*, DIEGG{ddagger} and DSGD§

1Steno Diabetes Center, DK-2820 Gentofte, Denmark, 2Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen Ø, Denmark and 3Department of Molecular Medicine, Karolinska Institute, SE-17176 Stockholm, Sweden

Received December 16, 2002; Accepted March 10, 2003

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=6.5x10-4 and Ptdt=2.4x10-4, 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=4.6x10-3, and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1x10-3. The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17ß-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.

* To whom correspondence should be addressed at: Steno Diabetes Center, 2 Niels Steensens Vej, DK-2820 Gentofte, Denmark. Tel: +45 44439101; Fax: +45 44438232; Email: tmpo{at}steno.dk

{dagger} The authors wish it to be known that, in their opinion, the first two should be regarded as joint First Authors.

{ddagger} The Danish IDDM Epidemiology and Genetics Group.

§ The Danish Study Group of IDDM in Childhood.


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