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      Association between -174G>C polymorphism in the IL-6 promoter region and the risk of obesity : A meta-analysis

      review-article
      , MD a , , MD a , , MD a , , MD b , , MD a , , PhD c , , PhD d ,
      Medicine
      Wolters Kluwer Health
      -174G>C polymorphism, IL-6, obesity

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          Abstract

          Background:

          Many researchers have suggested that the -174G>C polymorphism in the interleukin-6 (IL-6) promoter region contributes to the risk of obesity; however, this hypothesis is still inconclusive. Therefore, we conducted a meta-analysis to combine the data from several studies to arrive at a conclusion regarding the association between -174G>C polymorphism and the risk of obesity.

          Methods:

          The PubMed and Embase databases were searched up to February 20, 2018. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a random-effects model. Subgroup analysis and sensitivity were also performed.

          Results:

          Ten eligible studies involving 7210 cases were performed to identify the association strength. The association strength was measured by the ORs and 95% CIs. By pooling the eligible studies, we found a significant association between the -174G>C polymorphism and obesity risk (C vs G: OR = 1.37; 95% CI, 1.08–1.74; P heterogeneity < .01). Overall, individuals with the variant CC (OR = 1.58; 95% CI, 1.09–2.28; P heterogeneity < 0.01) and GC/CC (OR = 1.61; 95% CI, 1.13–2.29; P heterogeneity < .01) were associated with a significantly increased risk of obesity.

          Conclusion:

          The meta-analysis results suggested that the polymorphism -174G>C in the IL-6 promoter region was associated with a significantly increased risk of obesity.

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          Most cited references30

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          Interleukin-6 and Diabetes: The Good, the Bad, or the Indifferent?

          Inflammatory mechanisms play a key role in the pathogenesis of type 1 diabetes. Individuals who progress to type 2 diabetes display features of low-grade inflammation years in advance of disease onset. This low-grade inflammation has been proposed to be involved in the pathogenetic processes causing type 2 diabetes. Mediators of inflammation such as tumor necrosis factor-alpha, interleukin (IL)-1beta, the IL-6 family of cytokines, IL-18, and certain chemokines have been proposed to be involved in the events causing both forms of diabetes. IL-6 has in addition to its immunoregulatory actions been proposed to affect glucose homeostasis and metabolism directly and indirectly by action on skeletal muscle cells, adipocytes, hepatocytes, pancreatic beta-cells, and neuroendocrine cells. Here we argue that IL-6 action-in part regulated by variance in the IL-6 and IL-6alpha receptor genes-contributes to, but is probably neither necessary nor sufficient for, the development of both type 1 and type 2 diabetes. Thus, the two types of diabetes are also in this respect less apart than apparent. However, the mechanisms are not clear, and we therefore propose future directions for studies in this field.
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            High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator.

            To examine the possibility that interleukin-6 (IL-6) can act as a paracrine regulator in adipose tissue by examining effects on adipogenic genes and measuring interstitial IL-6 concentrations in situ. Circulating and interstitial IL-6 concentrations in abdominal and femoral adipose tissue were measured using the calibrated microdialysis technique in 20 healthy male subjects. The effects of adipose cell enlargement on gene expression and IL-6 secretion were examined, as well as the effect of IL-6 in vitro on gene expression of adiponectin and other markers of adipocyte differentiation. The IL-6 concentration in the interstitial fluid was approximately 100-fold higher than that in plasma, suggesting that IL-6 may be a paracrine regulator of adipose tissue. This was further supported by the finding that adding IL-6 in vitro at similar concentrations down-regulated the expression of adiponectin, aP2, and PPARgamma-2 in cultured human adipose tissue. In addition, gene expression and release of IL-6, both in vivo and in vitro, correlated with adipose cell size. These data suggest that IL-6 may be a paracrine regulator of adipose tissue. Furthermore, increased adipose tissue production of IL-6 after hypertrophic enlargement of the adipose cells may detrimentally affect systemic insulin action by inducing adipose tissue dysfunction with impaired differentiation of the pre-adipocytes and/or adipocytes and lower adiponectin.
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              Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus.

              Type 2 diabetes mellitus (T2DM) is a metabolic pro-inflammatory disorder characterized by chronic hyperglycemia and increased levels of circulating cytokines suggesting a causal role of inflammation in its etiology. Polymorphism of cytokine genes including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were studied in T2DM patients as well as in normal healthy controls. Genomic DNA was isolated from both T2DM patients and controls followed by quantification and genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using suitable primers. The genotypic, allelic and carriage rate frequency distribution in patients and controls were analyzed by SPSS (version 15.0). Odd ratios with 95 % confidence interval was determined to describe the strength of association by logistic regression model. Double and triple combinations of genotypes were analyzed by χ(2) test. Gene-gene interaction and linkage disequilibrium tests were performed using SHEsis software. Individually, IL-6, TNF-α and IL-10 did not show any association. In double combination, IL-6 -597 GA and TNF-α -308 GG genotypes increased the risk up to 21 times and in triple combination IL-6 -597 AA, TNF-α -308 GG and IL-10 -592 CA increased the risk of T2DM up to 314 times. In gene-gene interaction allele 'A' of all studied polymorphisms increased the risk of T2DM up to 1.41 times. Our results suggest that individuals having a haplotype combination of AA, GG and CA for IL-6, TNF-α and IL-10 gene polymorphisms will have higher susceptibility and be at greater risk of developing T2DM.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                August 2018
                17 August 2018
                : 97
                : 33
                : e11773
                Affiliations
                [a ]Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College
                [b ]Department of Oncology, Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
                [c ]Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine
                [d ]Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
                Author notes
                []Correspondence: Rui Chen, Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. (e-mail: unioncr@ 123456163.com ).
                Article
                MD-D-18-01671 11773
                10.1097/MD.0000000000011773
                6112883
                30113463
                9d197591-0756-45b5-b8fa-793cd66deeaa
                Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 20 March 2018
                : 12 July 2018
                Categories
                5500
                Research Article
                Systematic Review and Meta-Analysis
                Custom metadata
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                -174g>c polymorphism,il-6,obesity
                -174g>c polymorphism, il-6, obesity

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