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      Genetic Variants in Toll-Like Receptor 4 Gene and Their Association Analysis with Estimated Glomerular Filtration Rate in Mexican American Families

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          Abstract

          Background/Aim: Toll-like receptor 4 (TLR4) is one of the regulators of the innate immune response. Genetic variations in TLR4 have been associated with inflammatory diseases, including type 2 diabetes. However, to our knowledge, there are no reports on the role of variations in TLR4 in chronic kidney disease susceptibility. The objective of this study is to determine whether the genetic variants in TLR4 are associated with the estimated glomerular filtration rate (eGFR), a measure of renal function. Methods: To evaluate the association between TLR4 variants and eGFR, we used data obtained from 434 Mexican American participants from the San Antonio Family Diabetes/Gallbladder Study. GFR was estimated using the Modification of Diet in Renal Disease formula. The Asp(299)Gly (rs4986790) and Thr(399)Ile (rs4986791) variants of TLR4 were genotyped using the TaqMan assay. Association analyses between genotypes and eGFR were performed using the measured genotype approach. Results: Of the two genetic markers examined for association, only the Asp(299)Gly variant of TLR4 exhibited a nominally significant association with eGFR (p = 0.025) after accounting for the covariate effects of age and sex terms, diabetes, duration of diabetes, systolic blood pressure, body mass index, and antihypertensive treatment. Carriers of Gly299 had significantly decreased eGFR values. Although, the Thr(399)Ile variant failed to exhibit a statistically significant association with eGFR, the carriers of Ile399, however, showed a trend towards decrease in eGFR. Conclusion: We show for the first time that Asp(299)Gly variants of TLR4 are associated with decrease in renal function in Mexican Americans.

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          Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.

          The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.
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            Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I.

            TLR4 polymorphism replacing Asp-299 with Gly and Thr-399 with Ile (D299G/T399I) causes LPS hyporesponsiveness. TLR4(SNPs)·MD-2·LPS exhibits an agonistic 2:2:2 architecture. Local structural differences were observed around D299G, but not around T399I, SNP site. These local differences cause the modulation of surface properties of TLR4, which may affect ligand binding. This study provides structural evidence of the functionality of the mutant TLR4 carrying the SNPs. Toll-like receptor 4 (TLR4) and its coreceptor MD-2 recognize bacterial lipopolysaccharide (LPS) and signal the innate immune response. Two single nucleotide polymorphisms (SNPs) of human TLR4, D299G and T399I, have been identified and suggested to be associated with LPS hyporesponsiveness. Moreover, the SNPs have been proposed to be associated with a variety of infectious and noninfectious diseases. However, how the SNPs affect the function of TLR4 remains largely unknown. Here, we report the crystal structure of the human TLR4 (D299G/T399I)·MD-2·LPS complex at 2.4 Å resolution. The ternary complex exhibited an agonistic "m"-shaped 2:2:2 architecture that was similar to that of the human wild type TLR4·MD-2·LPS complex. Local structural differences that might affect the binding of the ligands were observed around D299G, but not around T399I, SNP site.
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              The Asp299Gly polymorphism alters TLR4 signaling by interfering with recruitment of MyD88 and TRIF.

              Asp(299)Gly (D299G) and, to a lesser extent, Thr(399)Ile (T399I) TLR4 polymorphisms have been associated with gram-negative sepsis and other infectious diseases, but the mechanisms by which they affect TLR4 signaling are unclear. In this study, we determined the impact of the D299G and T399I polymorphisms on TLR4 expression, interactions with myeloid differentiation factor 2 (MD2), LPS binding, and LPS-mediated activation of the MyD88- and Toll/IL-1R resistance domain-containing adapter inducing IFN-β (TRIF) signaling pathways. Complementation of human embryonic kidney 293/CD14/MD2 transfectants with wild-type (WT) or mutant yellow fluorescent protein-tagged TLR4 variants revealed comparable total TLR4 expression, TLR4-MD2 interactions, and LPS binding. FACS analyses with anti-TLR4 Ab showed only minimal changes in the cell-surface levels of the D299G TLR4. Cells transfected with D299G TLR4 exhibited impaired LPS-induced phosphorylation of p38 and TANK-binding kinase 1, activation of NF-κB and IFN regulatory factor 3, and induction of IL-8 and IFN-β mRNA, whereas T399I TLR4 did not cause statistically significant inhibition. In contrast to WT TLR4, expression of the D299G mutants in TLR4(-/-) mouse macrophages failed to elicit LPS-mediated induction of TNF-α and IFN-β mRNA. Coimmunoprecipitation revealed diminished LPS-driven interaction of MyD88 and TRIF with the D299G TLR4 species, in contrast to robust adapter recruitment exhibited by WT TLR4. Thus, the D299G polymorphism compromises recruitment of MyD88 and TRIF to TLR4 without affecting TLR4 expression, TLR4-MD2 interaction, or LPS binding, suggesting that it interferes with TLR4 dimerization and assembly of intracellular docking platforms for adapter recruitment.
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                Author and article information

                Journal
                CRM
                CRM
                10.1159/issn.1664-5502
                Cardiorenal Medicine
                Cardiorenal Med
                S. Karger AG (Basel, Switzerland karger@ 123456karger.com http://www.karger.com )
                1664-3828
                1664-5502
                August 2016
                20 May 2016
                : 6
                : 4
                : 301-306
                Affiliations
                aDivision of Nephrology, Department of Medicine, University of Texas Health Science Center, bDepartment of Genetics, Texas Biomedical Research Institute, and cSouth Texas Veterans Healthcare System, San Antonio, Tex., and dSouth Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Brownsville, Tex., and Edinburg, Tex., USA; eDepartment of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
                Article
                CRM2016006004301 PMC5020380 Cardiorenal Med 2016;6:301-306
                10.1159/000445754
                PMC5020380
                27648011
                16449004-5072-4d5d-ad64-a079bb6e230b
                © 2016 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 08 June 2015
                : 08 March 2016
                Page count
                Tables: 2, References: 21, Pages: 6
                Categories
                Original Paper

                Medicine,General social science
                Toll-like receptor 4,Asp(299)Gly,Thr(399)Ile,rs4986790,rs4986791,Estimated glomerular filtration rate,Mexican Americans

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