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.

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.


 * 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.


 * The development of bronchiolitis obliterans syndrome (BOS) after lung transplantation is more likely and happens earlier for rs1800795(G) carriers.


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


 * 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).


 * 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.


 * 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).


 * 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.


 * In 168 Brazilian patients, rs1800795(G) allele frequency was higher in gastric cancer than in patients with chronic gastritis.


 * 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).


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


 * 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). This was not seen in a Norwegian population.


 * 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.


 * The rs1800795(G) allele is more frequent in women with hyperandrogenism than in controls.


 * 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).


 * (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).

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.


 * 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.


 * 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.


 * 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).


 * 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.


 * 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.


 * 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.


 * 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).


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


 * 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).


 * The degree of periodontitis was more severe in rs1800795(C) carriers than (G) carriers.


 * 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.


 * 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.

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)

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.

rs1800795 coronary artery disease 190 affected Asian Indian sibling pairs