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Series GSE67784 Query DataSets for GSE67784
Status Public on Aug 09, 2016
Title A Gene Expression-based Blood Diagnostic for Symptomatic Transthyretin Amyloidosis Revealing Male and Female-specific Signatures
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g. when the TTR tetramer stabilizer tafamidis was administered to familial amyloid polyneuropathy (FAP) patients early in the disease course. When asked if the findings of the tafamidis registration trial were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit” the advisory committee said yes, but the FDA rejected the tetramer stabilization surrogate biomarker required for orphan tafamidis approval–hence, acceptable biomarkers are badly needed. Herein, we explored whether peripheral blood cell mRNA expression profiles could differentiate symptomatic from asymptomatic V30M FAP patients, and if such a profile would normalize upon tafamidis treatment. We demonstrate that blood cell gene expression patterns reveal sex-independent as well as male and female specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers, that normalize in FAP patients 6 months after tafamidis treatment. Thus these signatures have potential both as an early diagnostic and as a surrogate biomarker for measuring response to treatment in FAP patients.
Overall design Study Subjects: Tafamidis-treated and untreated V30M FAP patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations had whole blood drawn. RNA was extracted from a total of 309 peripheral blood samples collected in PAXgene tubes (Qiagen). RNA Extraction and Microarray Processing: RNA was extracted with the PAXgene RNA Whole Blood Kit. Each RNA sample (100ng) was amplified and labeled with the Ambion WT Express Kit and hybridized to Affymetrix HuGene 1.1 ST Arrays using the Affymetrix GeneTitan Multi-Channel (MC) platform. Normalized signals were generated using Robust Multichip Average (RMA) in Partek Genomics Suite software version 6.6. Probesets on the DNA microarrays with low expressed signals were determined using a kernel density plot, and signals <Log2 of 6 were excluded from analysis.
Web link
Contributor(s) Kurian SM
Citation(s) 27570551
Submission date Apr 12, 2015
Last update date Nov 08, 2016
Contact name Sunil Kurian
Phone 858-784-7759
Organization name The Scripps Research Institute
Department Molecular and Experimental Medicine
Street address 10550 N Torrey Pines Road
City La Jolla
State/province CA
ZIP/Postal code 92037
Country USA
Platforms (1)
GPL11532 [HuGene-1_1-st] Affymetrix Human Gene 1.1 ST Array [transcript (gene) version]
Samples (309)
GSM1655743 Control_001b
GSM1655744 Control_002b
GSM1655745 Control_003b
BioProject PRJNA280901

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE67784_RAW.tar 1.4 Gb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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