Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseasesReportar como inadecuado




Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseases - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Arthritis Research and Therapy

, 13:R69

First Online: 26 April 2011Received: 19 August 2010Revised: 28 February 2011Accepted: 26 April 2011

Abstract

IntroductionThe objective of this study is to determine if multiple systemic autoimmune diseases SAID share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders.

MethodsRNA microarray analyses Agilent Human 1AV2 20K oligo arrays were used to quantify gene expression in peripheral blood cells from 20 monozygotic MZ twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus SLE, six with rheumatoid arthritis RA, eight with idiopathic inflammatory myopathies IIM, and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects matched 2:1 to each twin by age, gender and ethnicity using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis.

ResultsProbands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes multiple-comparison adjusted P values < 0.1. Differentially expressed genes involved several overlapping pathways including immune responses 16%, signaling pathways 24%, transcription-translation regulators 26%, and metabolic functions 15%. Interferon IFN-response genes IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10 were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes 32% of the total probes as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes 81% whose expression differed significantly between probands and unrelated controls.

ConclusionsAlterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures.

AbbreviationsANOVAanalysis of variance

Cunrelated, matched control

DMdermatomyositis

FDRfalse discovery rate

GAPDHglyceraldehyde-3-phosphate dehydrogenase

GEOGene Expression Omnibus

GWASgenome-wide association study

IFNinterferon

IIMidiopathic inflammatory myopathy

IL-6interleukin-6

IPAingenuity pathways analysis

JDMjuvenile dermatomyositis

JPMjuvenile polymyositis

JRAjuvenile rheumatoid arthritis

MZmonozygotic

NF-κBnuclear factor-kappa-B

NIHNational Institutes of Health

Pproband

PCAprincipal component analysis

RArheumatoid arthritis

RQrelative quantitation

RQ-PCRrelative quantitation polymerase chain reaction

RT-PCRreal-time polymerase chain reaction

SAIDsystemic autoimmune disease

SLEsystemic lupus erythematosus

Uunaffected twin.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3330 contains supplementary material, which is available to authorized users.

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Autor: Terrance P O-Hanlon - Lisa G Rider - Lu Gan - Rick Fannin - Richard S Paules - David M Umbach - Clarice R Weinberg - R

Fuente: https://link.springer.com/







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