Genetic Variations at the — 174 G/C Polymorphism of the lnterleukin-6 Gene Promotor and Thyroid Disease

Zusammenfassung

Cytokines play a major role for the maintenance of tissue integrity in remodeling processes and the immune response to cancer. To determine the possible involvement of interleukin-6 (IL-6) in thyroid proliferative diseases, we have analyzed the allelic distributions of the — 174 G/C polymorphism in the IL-6 gene promotor. The G-polymorphism is associated with high, IL-1 inducible serum levels of IL-6, whereas the C-polymorphism results in significantly lower IL-6 expression. IL-6 haplotypes were obtained in a total of 450 patients from a region with intermediate iodine deficiency comprising 152 control patients without thyroid disease, 164 patients with multinodular goiter (MNG), 28 patients with follicular thyroid adenoma, and 106 patients with thyroid cancer, whereof 51 with papillary thyroid cancer (PTC), 10 with follicular thyroid cancer (FTC), and 34 with medullary thyroid cancer (MTC). Haplotyping of DNA from venous blood was performed by polymerase chain reaction, sequence-specific restriction enzyme cleavage of the amplimer by HSP 92 II and agarose gel electrophoresis. The control group displayed a CC-genotype frequency of 0.164 with a C allele frequency of 0.395. Goiter (0.164/0.427,p = 0.41) and thyroid adenoma (0.142/0.357,p = 0.60) showed an almost identical allele distribution, whereas thyroid cancer had a significantly higher frequency of the low-expression allele C (0.208/0.486, p = 0.04). Higher C-allele frequencies were identified in all types of thyroid cancer and reached significance in PTC (0.235/0.520, p = 0.03). Presence of the low-expression IL-6 allele C was significantly associated with increased tumor size (Tl + T2 vs. T3 + T4: CC genotype 0.105 vs. 0.262 p = 0.002; C allele 0.342 vs. 0.570, p = 0.004). Presence of the C-allele was also non-significantly associated with lymph node metastasis (NO vs. N +: C genotype 0.077 vs. 0.250 p = 0.26; C allele 0.346 vs. 0.509, p = 0.14). A relation to distant metastasis could not be examined due to small numbers. The correlations observed in this study support the possibility that IL-6 plays a role in mediating the immune response to thyroid cancer. They do not support a role of IL-6 in goiter formation.