Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?

BACKGROUND A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position -174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the -174 SNP for the induction of IL-6 in vivo. METHODS We vaccinated 20 and 18 healthy individuals homozygous for the -174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the blood at baseline and up to 24 h after vaccination. RESULTS Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1beta and TNF-alpha before or after vaccination. CONCLUSIONS The -174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

[1]  B. Weber,et al.  Interleukin-6 174G3C Polymorphism Is Associated with Improved Outcome in High-Risk Breast Cancer , 2003 .

[2]  Claudio Franceschi,et al.  Interleukin-6 gene alleles affect the risk of Alzheimer’s disease and levels of the cytokine in blood and brain , 2003, Neurobiology of Aging.

[3]  O. Wagner,et al.  The interleukin-6 G(-174)C promoter polymorphism does not determine plasma interleukin-6 concentrations in experimental endotoxemia in humans. , 2004, Clinical chemistry.

[4]  D. Seligson,et al.  Clinical Chemistry , 1965, Bulletin de la Societe de chimie biologique.

[5]  F. Green,et al.  Cooperative Influence of Genetic Polymorphisms on Interleukin 6 Transcriptional Regulation* , 2000, The Journal of Biological Chemistry.

[6]  R. Sacco,et al.  Carotid Intima-Media Thickness Is Associated With Allelic Variants of Stromelysin-1, Interleukin-6, and Hepatic Lipase Genes: The Northern Manhattan Prospective Cohort Study , 2002, Stroke.

[7]  I. Vauhkonen,et al.  The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity. , 2003, Diabetes.

[8]  S. Humphries,et al.  Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery. , 2004, Biochimica et biophysica acta.

[9]  J S Yudkin,et al.  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. , 1998, The Journal of clinical investigation.

[10]  G. O’Keefe,et al.  Interleukin-6 Promoter Haplotypes and Interleukin-6 Cytokine Responses , 2003, Shock.

[11]  A. Rumley,et al.  Interleukin-6 Gene −174G>C and −572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[12]  B. Nathwani,et al.  IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. , 2004, Blood.

[13]  C. Bouchard,et al.  Stromelysin-1 and Interleukin-6 Gene Promoter Polymorphisms Are Determinants of Asymptomatic Carotid Artery Atherosclerosis , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[14]  E. Gaetani,et al.  The -174 G/C polymorphism of the interleukin-6 gene promoter is associated with peripheral artery occlusive disease. , 2002, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[15]  E. Hawe,et al.  The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. , 2001, European heart journal.

[16]  R. Hanson,et al.  The interleukin-6 (−174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians , 2003, Human Genetics.

[17]  Aroon D. Hingorani,et al.  Acute Systemic Inflammation Impairs Endothelium-Dependent Dilatation in Humans , 1999, Circulation.

[18]  B. Weber,et al.  Interleukin-6 -174G-->C polymorphism is associated with improved outcome in high-risk breast cancer. , 2003, Cancer research.

[19]  G. Assmann,et al.  Effect of the interleukin-6 promoter polymorphism (−174 G/C) on the incidence and outcome of sepsis , 2002, Critical care medicine.

[20]  M. Laakso,et al.  Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. , 2003, Diabetes.

[21]  H. Möller,et al.  Interleukin‐6–174 G/C Promoter Gene Polymorphism C Allele Reduces Alzheimer's Disease Risk , 2003, Journal of the American Geriatrics Society.

[22]  The biological effects of interleukin 6 , 1996, Medicinal research reviews.

[23]  F. Burzotta,et al.  Relation of the -174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization. , 2001, The American journal of cardiology.

[24]  S. Humphries,et al.  Cortical bone resorption during exercise is interleukin-6 genotype-dependent , 2003, European Journal of Applied Physiology.

[25]  P. Delmas,et al.  Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study. , 2002, Bone.

[26]  H. Shin,et al.  Association of interleukin-6 promoter variant with bone mineral density in pre-menopausal women , 2003, Journal of Human Genetics.

[27]  S. Humphries,et al.  A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women. , 2001, Arthritis and rheumatism.

[28]  S. Humphries,et al.  Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population. , 2003, European heart journal.