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Journal article
TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers
Neurology, v 76(5), pp 467-474
01 Feb 2011
PMCID: PMC3034409
PMID: 21178100
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Objectives: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression.
Methods: We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls.
Results: In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 x 10(-5)) and controls (r = -0.49, p = 2.2 x 10(-10)).
Conclusions: In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD. Neurology (R) 2011;76:467-474
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- Title
- TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers
- Creators
- N. Finch - Mayo ClinicM. M. Carrasquillo - Mayo ClinicM. Baker - Mayo ClinicN. J. Rutherford - Mayo ClinicG. Coppola - University of California at Los AngelesM. DeJesus-Hernandez - Mayo ClinicR. Crook - Mayo ClinicT. Hunter - Mayo ClinicR. Ghidoni - Centro San Giovanni di Dio FatebenefratelliL. Benussi - Centro San Giovanni di Dio FatebenefratelliJ. Crook - Mayo ClinicE. Finger - Western UniversityK. J. Hantanpaa - Texas Medical CenterA. M. Karydas - University of California, San FranciscoP. Sengdy - University of British ColumbiaJ. Gonzalez - Mayo ClinicW. W. Seeley - University of California, San FranciscoN. Johnson - University of British ColumbiaT. G. Beach - Banner Sun Health Research InstituteM. Mesulam - University of British ColumbiaG. Forloni - Mario Negri Institute for Pharmacological ResearchA. Kertesz - Drexel UniversityD. S. Knopman - Mario Negri Institute for Pharmacological ResearchR. Uitti - Mayo ClinicC. L. White - Texas Medical CenterR. Caselli - Mayo Clinic, Scottsdale AZ.C. Lippa - Mayo Clinic in FloridaE. H. Bigio - Northwestern UniversityZ. K. Wszolek - Mayo ClinicG. Binetti - Centro San Giovanni di Dio FatebenefratelliI. R. Mackenzie - University of British ColumbiaB. L. Miller - University of California, San FranciscoB. F. Boeve - Mayo ClinicS. G. Younkin - Mayo ClinicD. W. Dickson - Mayo ClinicR. C. Petersen - University of California at Los AngelesN. R. Graff-Radford - Mayo ClinicD. H. Geschwind - University of California at Los AngelesR. Rademakers - Mayo Clinic
- Publication Details
- Neurology, v 76(5), pp 467-474
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 8
- Grant note
- P50 AG16574; U01 AG06576; R01 NS065782; R01 AG18023; RC1AG0356101; R01AG026938; AG19724; AG023501; AG1657303; AG25711; AG17216; AG03949; AG13854; DC008552; RC2NS070276; NS40256; NS057567; NS070276; 5P30AG012300 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Adelson Medical Research Foundation Tau Consortium Michael J. Fox Foundation for Parkinson's Research Association for Frontotemporal Dementia Winspear Family Center for Research on the Neuropathology of Alzheimer Disease Arizona Biomedical Research Commission Winspear Family Center for Research on the Neuropathology of Alzheimer's Disease Pacific Alzheimer's Disease Research Foundation 74580 / Canadian Institutes of Health Research Operating; Canadian Institutes of Health Research (CIHR) VIII/008724 / Delibera Hazel Soper Foundation Mayo Clinic Florida Research Committee P30 AG19610 / NIA (Arizona Alzheimer's Disease Core Center); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Allergan, Inc.; AbbVie; Allergan Arizona Alzheimer's Research Consortium CIHR; Canadian Institutes of Health Research (CIHR) Lawson Research Institute Michael Smith Foundation for Health Research Pacific Alzheimer Research Fund Robert and Clarice Smith Postdoctoral Fellowship Forest Laboratories, Inc. Eisai Inc.; Eisai Co Ltd Alzheimer's Association European Commission; European Commission Joint Research Centre Janssen; Johnson & Johnson; Johnson & Johnson USA; Janssen Biotech Inc Palumbo Professorship in Alzheimer's Disease Research UL1RR025741 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Pfizer Inc.; Pfizer Arizona Department of Health Services 211002 / Arizona Department of Health Services (Arizona Alzheimer's Research Center) Lawson Health Research Institute R01NS065782 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Easton Consortium Progetto Regione Lombardia; Regione Lombardia Medivation, Inc. Simons Foundation American Neurological Society Baxter International Inc. Cephalon, Inc.; Teva Pharmaceutical Industries Alzheimer's Society of London and Middlesex GE Healthcare; General Electric Amyotrophic Lateral Sclerosis Association 4001; 0011; 05-901; 1001 / Arizona Biomedical Research Commission CurePSP NIH/NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Elan Corporation Pacific Alzheimer Research Foundation (Canada) P50AG016573 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Avid Radiopharmaceuticals, Inc. R01DC008552 / NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Deafness & Other Communication Disorders (NIDCD) Novartis Potamkin Foundation Consortium for Frontotemporal Dementia Research Newmann Foundation James S. McDonnell Foundation Bayer Schering Pharma; Bayer AG University of Western Ontario Academic Development Fund 2009-2633 / Fondazione CARIPLO; Fondazione Cariplo Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program State of California Alzheimer's Center Danone; Danone Nutricia UCB; UCB Pharma SA McCune Foundation
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000287017500012
- Scopus ID
- 2-s2.0-79951494607
- Other Identifier
- 991019312474204721
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- Clinical Neurology