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
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
The authors wish it to be known that, in their opinion, the first two should be regarded as joint First Authors.
The Danish IDDM Epidemiology and Genetics Group.
The Danish Study Group of IDDM in Childhood.
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