− 174 G>C IL-6 polymorphism and primary iron overload in male patients
Primary iron overload (IO) is commonly associated with mutations in the hereditary hemochromatosis gene (HFE). Nonetheless, other genetic variants may influence the development of IO beyond HFE mutations. There is a single nucleotide polymorphism (SNP) at − 174 G>C of the interleukin (IL)-6 gene which might be associated with primary IO. Our aim was to study the association between the SNP − 174 G>C gene promoter of IL-6 and primary IO in middle-aged male patients. We studied 37 men with primary IO diagnosed by liver histology. Controls were age-matched male volunteers (n = 37). HFE mutations and the SNP − 174 G>C gene promoter of IL-6 were evaluated by PCR-RFLP. Logistic regression was used to evaluate the association between primary IO and SNP − 174 G>C gene promoter of IL-6. Patients and control subjects were in Hardy-Weinberg equilibrium for the SNP − 174 G>C gene promoter of IL-6 (p = 0.17). Significantly different genotype frequencies were observed between patients (43% CC, 43% CG, and 14% GG) and control subjects (10% CC, 41% CG, and 49% GG) (OR = 4.09, 95% CI = 2.06–8.13; p < 0.0001). The multiple logistic regression analysis showed that IO was significantly associated with CC homozygosis in the SNP − 174 G>C gene promoter of IL-6 (OR = 6.3, 95% CI = 1.9–21.4; p < 0.005) in a model adjusted by age and body mass index. In conclusion, CC homozygosis in the SNP − 174 G>C gene promoter of IL-6 can be proposed as one of the gene variants influencing iron accumulation in male adults with HFE mutations. Studies in larger cohorts are warranted.
KeywordsIron overload Inflammation IL-6 Polymorphism HFE Hemochromatosis
The authors wish to acknowledge the collaboration from the members of the Hospital de Clínicas “José de San Martín”, University of Buenos Aires.
Walter Tetzlaff, Tomas Meroño, Laura Boero, Eliana Botta, Maximiliano Martin, and Patricia Sorroche performed biochemical determinations and lipoprotein analyses. Walter Tetzlaff, Tomas Meroño, Laura Boero, Gloria Cerrone, Gustavo Frechtel, Fernando Brites, Jorge Rey, and Jorge Daruich contributed to the protocol design and data analysis. Jorge Daruich recruited patients and performed their clinical evaluation. Walter Tetzlaff, Marcelo Castro, Jorge Rey, Gloria Cerrone, and Gustavo Frechtel performed genetic testing. Walter Tetzlaff, Tomas Meroño, Gustavo Frechtel, Gloria Cerrone, and Fernando Brites contributed to writing the manuscript.
This work was supported in part by grants from the University of Buenos Aires (UBACyT CB23), CONICET (PIP 11220110100516), and National Agency for Scientific and Technological Promotion (PICT 2012-0418).
Compliance with ethical standards
The present study was carried out in accordance with the Declaration of Helsinki and the protocol was approved by the Ethics Review Board from the “José de San Martín” Clinical Hospital and from the Faculty of Pharmacy and Biochemistry, University of Buenos Aires.
Conflict of interest
The authors declare that they have no conflict of interest.
- 9.Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102(7):1369–1376CrossRefPubMedPubMedCentralGoogle Scholar
- 14.WHO/UNICEF/UNU. World Health Organization. (2003) [cited 2016 June 20]; Available from: http://www.who.int/nutrition/publications/obesity/WHO_TRS_916_spa.pdf?ua=1&ua=1
- 15.(2017) Standards of Medical Care in Diabetes—2017 Abridged for Primary Care Providers. Clin Diabetes 35(1):5–26Google Scholar
- 18.Rey J, Castro M, Lardo MM et al (2011) Análisis de las mutaciones del gen HFE relacionadas a hemocromatosis hereditaria en varones del área metropolitana de Buenos Aires. Implicancias en relación con características de la dieta habitual. Bioquímica y Patología Cliníca 75(3):13–17Google Scholar
- 19.Patel DN, King CA, Bailey SR, Holt JW, Venkatachalam K, Agrawal A, Valente AJ, Chandrasekar B (2007) Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 282(37):27229–27238CrossRefPubMedGoogle Scholar