IL-6 Haplotypes, Inflammation, and Risk for Cardiovascular Disease in a Multiethnic Dialysis Cohort

Liu, Yongmei; Berthier-Schaad, Yvette; Fallin, M. Danielle; Fink, Nancy E.; Tracy, Russell P.; Klag, Michael J.; Smith, Michael W.; Coresh, Josef

doi:10.1681/asn.2005050465

Cited by 115 publications

(74 citation statements)

References 38 publications

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“…The C-allele of the IL6 À174G4C promoter polymorphism has been shown to be associated with CRP or IL-6 levels, but the relationship between À174G4C promoter polymorphism and risk of cardiovascular diseases is inconsistent in the different studies. [39][40] On the other hand, two recent studies in Chinese Han population demonstrate that IL-6 gene À572G allele is associated with higher risk for coronary heart disease and myocardial infarction, and is related to higher expression of IL-6 from peripheral blood mononuclear cells. 41,42 In addition, the À572CG genotype has also been shown to be predictive of IL-6 levels above 5 ng/l in patients with a subsequent cardiovascular event.…”

Section: Discussionmentioning

confidence: 99%

Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension

et al. 2007

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Hypertension is an important risk factor for cardiovascular diseases. There is increasing evidence suggesting that inflammation is involved in the development of hypertension. Interleukin-6 (IL-6) is an important mediator of inflammatory response and the major regulator of hepatic production of acute phase proteins, such as fibrinogen and C-reactive protein (CRP), which have been associated with hypertension and cardiovascular diseases. Therefore, we studied the association of single nucleotide polymorphism (SNP) in the IL-6 gene (IL6) promoter with plasma levels of fibrinogen, CRP and hypertension. Five hundred and two Hong Kong Chinese subjects (282 normotensives and 220 hypertensives) were recruited. IL-6 gene promoter was examined for polymorphism and the study subjects were genotyped for any SNP identified. The IL6 À572C4G polymorphism (rs1800796) was found with a frequency of 0.23 for the minor G allele. Subjects with the À572G allele had significantly higher plasma fibrinogen (3.0670.57 vs 2.8370.60, P ¼ 0.002) and CRP (interquartile range 0.33-1.56 vs 0.12-0.93, P ¼ 0.003) levels than those without. The À572C4G polymorphism was found to be an independent predictor of fibrinogen and CRP levels after adjusting for confounding factors. Plasma concentrations of fibrinogen and CRP correlated with systolic blood pressure. However, the À572C/G genotype frequencies did not differ between hypertensive and normotensive subjects, and there was no association between À572C4G polymorphism and blood pressure. Our results provide evidence that there is a clear genetic influence of IL6 À572C4G polymorphism on plasma levels of fibrinogen and CRP, but this polymorphism does not lead to elevated blood pressure.

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Section: Discussionmentioning

confidence: 99%

Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension

et al. 2007

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“…Because transmission of genes is a random phenomenon, gene polymorphisms modulating IL-6 synthesis may represent an unbiased means for testing whether the link between IL-6 and CV outcomes in patients with CKD is causal (Mendelian randomization). The 2174 G/C single-nucleotide polymorphism is a functional variant located in the promoter region of the IL-6 gene that regulates the rate of IL-6 gene transcription (22)(23)(24)(25)(26)(27)(28) and therefore represents a reliable research tool for testing the nature (causal versus noncausal) of the link between IL-6 and CV outcomes in CKD. With this background in mind, we set out to confirm findings by Barreto et al (21) in a large observational study with a carefully characterized cohort of 755 patients with stages 2-5 CKD and to test whether this relationship may underlie a causal link by applying the Mendelian randomization approach (i.e., by stratifying the study population according to the functional 2174 G/C polymorphism in the IL-6 gene).…”

Section: Introductionmentioning

confidence: 99%

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Spoto

Mattace-Raso

Sijbrands

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives High serum IL-6 is a major risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patients with CKD, but it is still unknown whether the link between IL-6 and CVD in CKD is causal in nature.Design, setting, participants, & measurements In a cohort of 755 patients with stages 2-5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up6SD, 31610 months) and used the functional polymorphism (2174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal.Results In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P,0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the 2174 G/C polymorphism had higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95% CI, 1.15 to 4.00; P=0.02) as well as a 87% higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes. ConclusionsIn patients with stages 2-5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the 2174 G/C polymorphism in the IL-6 gene suggests that IL-6 may be causally involved in the high CV risk in this population.

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“…There are increasing experimental data showing that three SNPs -174G/C (rs1800795), -572C/G (rs1800796) and -6331T/C (rs10499563) and several haplotypes of the IL-6 gene are not only related to levels of plasma IL-6 but also to inflammation (10)(11)(12)(13)(14). Moreover, the IL-6 gene polymorphism is suggested to participate in the pathogenesis of obesity and modify the risk of developing obesity-related metabolic disorders, especially insulin resistance (15,16).…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in interleukin-6 modified risk of obstructive sleep apnea syndrome

Zhang

Liu²,

Li³

et al. 2009

Int J Mol Med

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Abstract. Obesity and inflammation are known to correlate with the pathogenesis of obstructive sleep apnea syndrome (OSAS). Interleukin (IL)-6, an important regulator of obesity and inflammation, was reported to phenotypically increase in patients with OSAS. This study aimed to investigate whether genetic variants in IL-6 confer susceptibility to OSAS. The study population consisted of 151 patients with OSAS and 75 healthy controls from Southeast China. Five haplotype-tagging single nucleotide polymorphisms (tSNPs) were selected across 21 kb of the IL-6 locus using Haploview software V4.1. The tSNPs were amplified by polymerase chain reaction (PCR) and genotyped by restriction enzyme digestion followed by gel electrophoresis. Linkage disequilibrium (LD) and haplotype reconstruction were carried out by means of a SHEsis program. No distribution difference of any of the five tSNPs between OSAS patients and controls was observed. However, in nonobese individuals (n=117), the minor allele G (rs1800796) decreased risk of OSAS compared with the major allele C [odds ratio (OR), 0.48; 95% confidence interval (CI), 0.26-0.86; p=0.014], and the haplotype TG (rs1880242, rs1800796) conferred a significantly decreased risk of OSAS than single allele G (rs1800796) (OR, 0.39; 95% CI, p=0.003). Moreover, the severity of sleep-disordered breathing (measured by apnea hypopnea index) increased linearly in carriers of the C variant of IL-6 -572G/C polymorphism (14.3±5.1, 22.0±3.6 and 34.8±3.5 for GG, CG and CC, respectively; p=0.012). To the best of our knowledge, this is the first study to suggest that genetic variants in IL-6 could modify OSAS susceptibility. SNP genotyping of IL-6 is a potential strategy for detecting the risk of breathing disordered diseases in non-obese individuals.

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IL-6 Haplotypes, Inflammation, and Risk for Cardiovascular Disease in a Multiethnic Dialysis Cohort

Cited by 115 publications

References 38 publications

Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension

Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Genetic variants in interleukin-6 modified risk of obstructive sleep apnea syndrome

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