Association of a functional 17beta-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, 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.
Steno Diabetes Center, DK-2820 Gentofte, Denmark.
Ole P
OP
Kristiansen
Runa L
RL
Nolsøe
Lykke
L
Larsen
Anette M P
AM
Gjesing
Jesper
J
Johannesen
Zenia M
ZM
Larsen
Anne E
AE
Lykkesfeldt
Allan E
AE
Karlsen
Flemming
F
Pociot
Thomas
T
Mandrup-Poulsen
D017668:Age of Onset; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012737:Sex Factors
D015850:Interleukin-6; D004958:Estradiol