Screening the human serum proteome for genotype–phenotype associations: An analysis of the IL6 –174G&gt;C polymorphism

Hegedus, Christine; Skibola, Christine F.; Bracci, Paige M.; Holly, Elizabeth A.; Smith, Martyn T.

doi:10.1002/pmic.200600366

Cited by 21 publications

(18 citation statements)

References 46 publications

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“…Recently, a substantial improvement of RA upon treatment with anti-IL-6 receptor antibody [6]. The IL6 G/G genotype is associated with increased IL-6 levels compared to the C/C genotype, contributing to the complex regulation of IL-6 production [26,51-53]. Furthermore, IL-6 expression in synovial tissue is higher in end-stage RA than in chronic active RA [54].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study

et al. 2011

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BackgroundVarious cytokines and inflammatory mediators are known to be involved in the pathogenesis of rheumatoid arthritis (RA). We hypothesized that polymorphisms in selected inflammatory response and tissue repair genes contribute to the susceptibility to and severity of RA.MethodsPolymorphisms in TNFA, IL1B, IL4, IL6, IL8, IL10, PAI1, NOS2a, C1INH, PARP, TLR2 and TLR4 were genotyped in 376 Caucasian RA patients and 463 healthy Caucasian controls using single base extension. Genotype distributions in patients were compared with those in controls. In addition, the association of polymorphisms with the need for anti-TNF-α treatment as a marker of RA severity was assessed.ResultsThe IL8 781 CC genotype was associated with early onset of disease. The TNFA -238 G/A polymorphism was differentially distributed between RA patients and controls, but only when not corrected for age and gender. None of the polymorphisms was associated with disease severity.ConclusionsWe here report an association between IL8 781 C/T polymorphism and age of onset of RA. Our findings indicate that there might be a role for variations in genes involved in the immune response and in tissue repair in RA pathogenesis. Nevertheless, additional larger genomic and functional studies are required to further define their role in RA.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study

et al. 2011

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“…Indeed, a recent proteomic screen of the human serum from 151 healthy men identified apolipoprotein C1 and HSP60 as circulating proteins whose serum levels were significantly associated with IL6 Ϫ174 genotypes. 43 These data raise the possibility that sequence variation in the IL6 gene may have pleiotropic effects on multiple yet-unrecognized protein components or pathways, which may be of importance to pathogenesis of brain small vessel disease.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain

Fornage

Chiang

O’Meara

et al. 2008

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Background and Purpose-To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study. Methods-Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (nϭ532) and Whites (nϭ2905). Results-Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the Ϫ174G/C promoter polymorphism was associated with an increased risk of WML (ORϭ1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the Ϫ572G/C promoter polymorphism was associated with an increased risk of BI (ORϭ1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race. Conclusions-This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

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“…The polymorphisms were selected for analysis on the basis that they are either known to or are likely to cause a functional change in the gene of interest. As such, they are widely considered to be important in determining the levels of the corresponding cytokines in vivo, though we note that efforts to firmly establish these genotype-phenotype relationships are ongoing [57][58][59][60] . A few of the polymorphisms have been previously investigated in genetic studies of depressive disorders, while others have been investigated for the first time here.…”

Section: Introductionmentioning

confidence: 99%

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and Childhood-Onset Mood Disorders

et al. 2008

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Background/Aims: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. Methods: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. Results: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. Conclusion: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

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Screening the human serum proteome for genotype–phenotype associations: An analysis of the IL6 –174G>C polymorphism

Cited by 21 publications

References 46 publications

Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study

Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study

Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain

Cytokine Genes <i>TNF</i>, <i>IL1A</i>, <i>IL1B</i>, <i>IL6</i>, <i>IL1RN</i> and <i>IL10</i>, and Childhood-Onset Mood Disorders

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