Rs1800795

rs1800795 is a SNP in the promoter of the interleukin-6 IL6 gene, affecting the levels made of this important cytokine. In the literature, it is almost universally referred to as the IL6 "-174" polymorphism. It tends to be quite polymorphic in Caucasians, but Asian and African populations are almost monomorphic (for the (G) allele).

It was first described in 1998, when it was shown that the rs1800795(C) allele produces less IL6 than the (G) allele, which supported the hypothesis that a protective genotype against systemic onset juvenile rheumatoid arthritis would be rs1800795(C;C), and indeed, few juvenile RA patients had that genotype.[PMID 9769329]

Studies on rs1800795 now include potential associations with heart disease, Kaposi's sarcoma, type-2 diabetes, stroke, obesity, Hodgkin's lymphoma, sudden infant death syndrome, cancer (including breast cancer, gastric cancer, prostate cancer), hypertension, periodontitis, and complications arising after organ transplantations or grafts. It is worth noting that some of the associations seen for rs1800795 alleles are not for the risk of developing a given disorder; instead, they relate to how a disorder might progress or respond to various treatments. Summaries of several major associations are available at OMIM.

The rs1800795(G) allele, generally associated with higher levels of IL6, has been associated with increased risk in the following studies:

• The rs1800795(G) allele was significantly associated with type-2 diabetes (odds ratio 1.51, CI: 1.11-2.07, p=0.0096) in a study of 700 elderly Caucasians.[PMID 15472205]

• Following a kidney transplant, patients with rs1800795(G;G) genotypes have a higher risk of new-onset diabetes and higher C-reactive protein levels) compared to the (C;C) genotype. Since this was more pronounced in overweight patients, the authors suggest that diabetes-inducing drug administration should be limited in overweight patients who are rs1800795(G;G) following renal transplantation.[PMID 16837641]

• The development of bronchiolitis obliterans syndrome (BOS) after lung transplantation is more likely and happens earlier for rs1800795(G) carriers.[PMID 12451269]

• Among HIV+ men, the lifetime risk of developing Kaposi sarcoma is higher for rs1800795(G;G) homozygotes compared to (C;C) homozygotes.[PMID 11001912]

• Patients with Hodgkin's lymphoma who are rs1800795(G;G) were less likely to be successfully treated, with odds ratios for failure of 1.75 (CI: 1.04-2.92, p=0.03).[PMID 17496310]

• A study of 139 elderly males with acute coronary syndrome (ACS) indicated that rs1800795(G;G) genotypes were at 3.89 fold (CI: 1.71-8.86, p=0.001) higher risk of dying within one year of their ACS event than (C;G) or (C;C) genotypes.[PMID 16098388]

• Although the odds of having a stroke weren't different, among patients (in this case, under 60 years of age) who did have a stroke those with a rs1800795(G;G) genotype had more severe disability after 1 week (odds ratio 3.2, CI: 1.5-6.6, p=0.002).[PMID 14512079]

• Among Chinese patients with hypertension, the rs1800795(G) allele is more common, and (G;G) genotypes had significantly higher plasma PAI-1 activity than (C;C) genotypes.[PMID 15831362]

• In 168 Brazilian patients, rs1800795(G) allele frequency was higher in gastric cancer than in patients with chronic gastritis. [PMID 17560462]

• Although the odds of having Crohn's disease aren't affected, among 153 children with it, those with the rs1800795(G;G) genotype were more growth-retarded at diagnosis than (C;G) or (C;C) genotypes. (G;G) patients also had higher circulating levels of C-reactive protein (CRP).[PMID 16150725]

• rs1800795(G) carriers don't increase their high-density lipoprotein (HDL) levels after 24 weeks of aerobic exercise as much as rs1800795(C) carriers.[PMID 15904871]

• The rs1800795(G;G) genotype was more frequent in Australian infants with sudden infant death syndrome (58%) than in control subjects (38%, p=0.02).[PMID 17055359] This was not seen in a Norwegian population.[PMID 17509454]

• Women with endometriosis who are rs1800795(G) carriers appear to be more likely to develop chocolate cysts, and (G) allele carriers may be at slightly higher risk of developing endometriosis.[PMID 12517591]

• The rs1800795(G) allele is more frequent in women with hyperandrogenism than in controls.[PMID 11889177]

• Children with the rs1800795(G;G) genotype are more likely to have recurrent acute otitis, based on a study of 348 patients, with an odds ratio of 1.64 (p=0.02).[PMID 17908769]

• (G) allele is increased risk ((C) allele is decreased risk) for type-2 diabetes; this SNP is one of 4 relatively common SNPs reported to represent risk for type-2 diabetes in the DESIR prospective study of 3,877 Caucasian participants. Under an additive model, the odds ratio for rs1800795(C) carriers is 0.79 (CI: 0.65-0.96, p=0.01). For the 4 SNPs, each risk allele increased type-2 diabetes risk by 1.34x (p=2x10e-6), with an odds ratio of 2.48 (CI: 1.59-3.86) for carriers of 4 or more compared to those with one or none (risk alleles).[PMID 17977958]

The rs1800795(C) allele, generally associated with lower levels of IL6, has been associated with increased risk in these studies:

• rs1800795 (C;C) and (C;G) Caucasians who are excessively heavy (body mass index ~33 +/- 5kg/m2) are at increased risk (odds ratio 5.2, p=0.003) for developing obesity-related metabolic disorders such as hypertension, atherogenic dyslipidemia, and insulin resistance.[PMID 17998015]

• Among 571 patients with type-2 diabetes, the rs1800795(C) allele is correlated with higher body mass index, but it showed no correlation among non-diabetics.[PMID 15172007]

• A study of 238 Caucasians with type-2 diabetes concluded that rs1800795(C) carriers have an insulin resistance "IL-6-sensitive" phenotype and perhaps strategies to manage insulin resistance should be different between (C) carriers vs. (G;G) patients.[PMID 16140413]

• In patients with end-stage renal disease (ESRD) being treated by hemodialysis, rs1800795(C) allele carriers had higher diastolic blood pressure (p=0.008) and a higher left ventricular mass index (p=0.026) than (G;G) homozygotes. Among diabetic patients in dialysis, the prevalence of left ventricular hypertrophy in (C) allele carriers was 87.5% vs. 36.3% among (G;G) genotypes (p= 0.02).[PMID 12846758]

• Among recipient of a kidney transplant, rs1800795(C) allele carriers had worse three-year graft survival (71/104 = 68.3%; p=0.0059) with a 3.7-fold increased relative risk of graft loss compared to rs1800795(G;G) genotypes (48/54 = 88.9%). The authors suggest that determining the rs1800795 genotype may offer a new method for identifying patients at increased risk of allograft loss.[PMID 12371985]

• Among prostate cancer patients, the rs1800795(C) allele is associated with more aggressive cancer and higher prostate-specific antigen levels compared to rs1800795(G;G) homozygotes.[PMID 16006970]

• Although the rs1800795(C) allele was not associated with a higher frequency of heart attacks, it did have an association with inflammation and infarcts detectable only by MRI, suggesting that rs1800795(C) may chronically predispose an individual to develop atherosclerosis.[PMID 12482836]

• The combination of carrying at least one rs1800795(C) and one rs1205(T), a SNP in the C-reactive protein gene, led to higher risk of a stroke after cardiac surgery (odds ratio 3.3, CI: 1.4-8.1, p=0.0023) compared to individuals who were rs1800795(G;G) and rs1205(C;C).[PMID 16051899]

• The rs1800795(C) allele was associated with higher postoperative IL6 levels and a less favorable clinical outcome following coronary revascularization surgery.[PMID 16183563]

• The rs1800795(C;C) genotype was significantly higher in the group of 122 adult periodontitis patients than in controls (odds ratio 1.896, CI: 1.1-3.2, p=0.0283).[PMID 17209781]

• The degree of periodontitis was more severe in rs1800795(C) carriers than (G) carriers.[PMID 17286759]

• The rs1800795(C) allele was over-represented in patients with Alzheimer's disease compared to controls and the (C;C) genotype was associated with higher risk in women.[PMID 12928051]

• The rs1800795(C) allele was higher in non-survivors compared to (nonagenarian) survivors in a case/control study of ~100 pairs of matched Finnish individuals; to put it another way, the rs1800795(G) allele may be associated with increased longevity.[PMID 15664628]

[PMID 18257935] rs1800797, rs1800796 and rs1800795 have been shown to affect both the transcription and secretion of IL-6, to symptomatic distal interphalangeal osteoarthritis based on 535 women. the G alleles of two promoter single-nucleotide polymorphisms (SNP) G-597A and G-174C were more common among the subjects with symptomatic DIP OA than among those with no disease (p-values corrected for multiple testing 0.020 and 0.024). Also, the carriage of at least one G allele in these positions increased the risk of disease (p=0.006 and, p=0.008, respectively). Carrying a haplotype with the G allele in all three promoter SNPs increased the risk of symptomatic DIP OA more than four-fold (OR 4.45, p=0.001). Carriage of the G-G diplotype indicated an increased risk of both symmetrical DIP OA (OR 1.52 95% CI 1.01 to 2.28) and symptomatic DIP OA (OR 3.67 95% CI 1.50 to 9.00)

[PMID 18056967] Suggests that "healthy elderly individuals may have a proinflammatory profile playing as a downregulating factor for inducible Hsp70, particularly if -174 G/C-negative" and that therefore, a nutraceutical intervention (fermented papaya preparation 9 g/day) might be of benefit.

[PMID 18449426] rs1800795 coronary artery disease 190 affected Asian Indian sibling pairs

[PMID 19280716] The IL6-174G/C polymorphism is associated with celiac disease susceptibility in girls.

[PMID 19435922] Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer

[PMID 19671870] Prognostic Significance of Interleukin-6 Single Nucleotide Polymorphism Genotypes in Neuroblastoma: rs1800795 (Promoter) and rs8192284 (Receptor)

[PMID 19452524] Tumor markers and rectal cancer: support for an inflammation-related pathway

[PMID 19387461] Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection

[PMID 19833146] Sex-specific effects of CNTF, IL6 and UCP2 polymorphisms on weight gain

[PMID 19853505] The -174 G/C polymorphism of the IL6 gene is associated with elite power performance

[PMID 20043205] Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25,703 subjects

[PMID 20132806] Study of TNFalpha -308 G/A and IL6 -174 G/C polymorphisms in type 2 diabetes and obesity risk in the Tunisian population

[PMID 20149313] Interleukin-6 gene -174 promoter polymorphism is associated with endothelial dysfunction but not with disease susceptibility in patients with rheumatoid arthritis

[PMID 20176930] Computational identification of gene-social environment interaction at the human IL6 locus

[PMID 20175976] A meta-analysis of interleukin-6 promoter polymorphisms on risk of hip and knee osteoarthritis

[PMID 20044998] Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis

[PMID 20592333] The increased plasma C-reactive protein and interleukin-6 levels in patients undergoing coronary artery bypass grafting surgery are associated with the interleukin-6-174G > C gene polymorphism

[PMID 20333461] Serum CRP and IL-6, genetic variants and risk of colorectal adenoma in a multiethnic population

[PMID 21291465] The association of genetic polymorphisms with cerebral palsy: a meta-analysis

[PMID 21736829] Gene-PUFA interactions and obesity risk

[PMID 21889771] Lack of association between IL6 single nucleotide polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis

[PMID 22015309] MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction

[PMID 22107760] Genetic susceptibility of intervertebral disc degeneration among young Finnish adults

[PMID 22115178] Insulin-like growth factor 1 receptor polymorphism rs2229765 and circulating interleukin-6 level affect male longevity in a population-based prospective study (Treviso Longeva- TRELONG)

[PMID 20459474] Can we predict top-level sports performance in power vs endurance events? A genetic approach

[PMID 22282500] Evaluation of published single nucleotide polymorphisms associated with acute graft versus host disease

[PMID 22459738] Genetic and Immunological Evidence Implicates Interleukin 6 as a Susceptibility Gene for Leprosy Type 2 Reaction

[PMID 21552154] Common genetic variation in the IGF1 associates with maximal force output

[PMID 22475653] Genetic predictors of fatigue in prostate cancer patients treated with androgen deprivation therapy: Preliminary findings

[PMID 22571276] Interleukin-6 promoter polymorphism and plasma levels in patients with schizophrenia