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Interleukin-6 receptor gene, plasma C-reactive protein, and diabetes risk in women.

ABSTRACT: Recent genome-wide association studies (GWASs) related common variants in the interleukin-6 (Il-6) receptor (IL6R) gene to plasma C-reactive protein (CRP) concentrations. Because IL6R variants were previously associated with IL-6 levels, we tested whether the associations with CRP were independent of IL-6 and the interactions between IL6R variants and CRP in relation to diabetes risk.Plasma CRP and IL-6 levels and 10 IL6R polymorphisms were determined in a nested case-control study of 633 diabetic and 692 healthy Caucasian women.In both nondiabetic and diabetic women, IL6R polymorphisms were associated with plasma CRP levels, independent of IL-6 concentration. After adjustment of IL-6 levels, CRP concentrations in the genotype AA, AC, and CC of the GWAS polymorphism rs8192284 were 0.32, 0.26, and 0.24 pg/ml, respectively, among nondiabetic women (P for trend = 0.003; false discovery rate [FDR] = 0.01) and 0.63, 0.48, and 0.43 pg/ml among diabetic women (P for trend <0.0001; FDR = 0.0001). Haplotypes inferred from polymorphisms within a linkage disequilibrium block including rs8192284 were also significantly associated with CRP levels (P = 0.0002). In an exploratory analysis, rs8192284 showed significant interactions with CRP levels in relation to diabetes risk (P for interaction = 0.026). The odds ratios across increasing quartiles of CRP were 2.19 (95% CI 1.42-3.36), 2.03 (1.27-3.23), and 2.92 (1.77-4.82) in the carriers of allele-C and 2.21 (1.18-4.12), 3.77 (1.87-7.57), and 5.02 (2.4-10.5) in the noncarriers.IL6R variants were significantly associated with plasma CRP, independent of IL-6 levels. IL6R variants may interact with CRP in predicting diabetes risk.

SUBMITTER: Qi L

PROVIDER: S-EPMC2606885 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Interleukin-6 receptor gene, plasma C-reactive protein, and diabetes risk in women.

Qi Lu L Rifai Nader N Hu Frank B FB

Diabetes 20081013 1

<h4>Objective</h4>Recent genome-wide association studies (GWASs) related common variants in the interleukin-6 (Il-6) receptor (IL6R) gene to plasma C-reactive protein (CRP) concentrations. Because IL6R variants were previously associated with IL-6 levels, we tested whether the associations with CRP were independent of IL-6 and the interactions between IL6R variants and CRP in relation to diabetes risk.<h4>Research design and methods</h4>Plasma CRP and IL-6 levels and 10 IL6R polymorphisms were d ...[more]

PMID: 18852330

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Project description:BackgroundPrevious studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking.MethodsAssociations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case-control study. Results were validated in 532 case patients and 595 control subjects in a nested case-control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model.ResultsSerum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%).ConclusionsAlthough increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer.

Project description:Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia. Women who develops hyperglycemia for the first time during pregnancy receive the diagnosis gestational diabetes mellitus (GDM). Presently, there is no consensus about the diagnostic criteria for GDM. A majority of these women subsequently develop postpartum overt diabetes making it important to identify these patients as early as possible. In this study we investigated if plasma levels of the interleukin-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1 signaling, can be used as a complementary biomarker for diagnosing GDM and predicting postpartum development of overt diabetes mellitus. Patients participating in this study (n = 227) were diagnosed with their first GDM 2004-2013 at Lund University Hospital, Lund, Sweden. Healthy pregnant volunteers (n = 156) were recruited from women's welfare centers in the same region 2014-2015. Levels of IL-1Ra and C-peptide were analyzed in ethylenediaminetetraacetic acid (EDTA)-plasma or serum using enzyme linked immunosorbent assay (ELISA). GDM patients had significantly lower levels of IL-1Ra than the control group (p = 0.012). In addition, GDM patients that had developed impaired glucose tolerance (IGT) or type 2 diabetes mellitus postpartum had significantly lower levels of IL-1Ra, and significantly higher levels of C-peptide than GDM patients that had not developed diabetes mellitus postpartum (p = 0.023) and (p = 0.0011) respectively. An inverse correlation was found between IL-1Ra and serum C-peptide levels in the control group (rs = -0.31 p = 0.0001). Our results show that IL-1Ra might be included in a future panel of biomarkers, both for diagnosing GDM to complement blood glucose, and also identifying GDM patients that are at risk of developing type 2 diabetes mellitus postpartum. However, the ROC curve analysis provided a sensitivity of 52.2% and specificity of 67.1%, which nonetheless may not be sufficient enough to use IL-1Ra as a sole biomarker.

Project description:BACKGROUND:C-reactive protein (CRP) is a well-recognized biomarker of inflammation, which can be used as a predictor of cardiovascular disease. Evidence have suggested exposure to multiple metals/metalloids may affect immune system and give rise to cardiovascular disease. However, it is lack of study to comprehensively evaluate the association of multiple metals and CRP, the interactions between metals, and the gene-metal interaction in relation to CRP levels. AIMS:To explore the associations of multiple plasma metals with serum CRP, and to test the interactions between metals, and gene-metal interactions on the levels of serum CRP. METHODS:We included 2882 participants from the Dongfeng-Tongji cohort, China, and measured 23 plasma metals and serum CRP concentrations. The genetic risk score (GRS) was calculated based on 7 established CRP-associated variants. For metals which were associated with the levels of CRP, we further tested the interactions between metals on CRP, and analyzed the gene-metal interactions on CRP. RESULTS:The median level for CRP in the total population was 1.17 mg/L. After multivariable adjustment, plasma copper was positively associated with serum CRP (FDR < 0.001), whereas selenium was negatively associated with serum CRP (FDR = 0.01). Moreover, selenium and zinc attenuated the positive association between high plasma copper and CRP (P for interaction < 0.001). Participants with a higher GRS had a higher CRP level, with the increase in ln-transformed CRP per increment of 5 risk alleles were 0.64 for weighted GRS, and 0.54 for unweighted GRS (both P < 0.001). Furthermore, the genetic association with CRP was modified by copper concentration (P for interaction < 0.001). CONCLUSIONS:Our results suggest that serum CRP is positively associated with plasma concentration of copper, and inversely associated with selenium. Plasma zinc, selenium and CRP genetic predisposition would modify the associations between plasma copper and serum CRP.

Dataset Information

Interleukin-6 receptor gene, plasma C-reactive protein, and diabetes risk in women.

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Interleukin-6 receptor gene, plasma C-reactive protein, and diabetes risk in women.

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