Browsing by Subject "HLA"

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    Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
    (Springer, 2019-02-09) Pottier, Cyril; Ren, Yingxue; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; van Rooij, Jeroen G. J.; Murray, Melissa E.; Christopher, Elizabeth; McDonnell, Shannon K.; Fogarty, Zachary; Batzler, Anthony; Tian, Shulan; Vicente, Cristina T.; Matchett, Billie; Karydas, Anna M.; Hsiung, Ging-Yuek Robin; Seelaar, Harro; Mol, Merel O.; Finger, Elizabeth C.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Matthis, Carlo; Prudlo, Johannes; Rizzu, Patrizia; Simon-Sanchez, Javier; Edbauer, Dieter; Roeber, Sigrun; Diehl-Schmid, Janine; Evers, Bret M.; King, Andrew; Mesulam, M. Marsel; Weintraub, Sandra; Geula, Changiz; Bieniek, Kevin F.; Petrucelli, Leonard; Ahern, Geoffrey L.; Reiman, Eric M.; Woodruff, Bryan K.; Caselli, Richard J.; Huey, Edward D.; Farlow, Martin R.; Grafman, Jordan; Mead, Simon; Grinberg, Lea T.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Snowden, Julie; Mann, David; Ertekin-Taner, Nilufer; Uitti, Ryan J.; Wszolek, Zbigniew K.; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Hodges, John R.; Piguet, Olivier; Geier, Ethan G.; Yokoyama, Jennifer S.; Rissman, Robert A.; Rogaeva, Ekaterina; Keith, Julia; Zinman, Lorne; Tartaglia, Maria Carmela; Cairns, Nigel J.; Cruchaga, Carlos; Ghetti, Bernardino; Kofler, Julia; Lopez, Oscar L.; Beach, Thomas G.; Arzberger, Thomas; Herms, Jochen; Honig, Lawrence S.; Vonsattel, Jean Paul; Halliday, Glenda M.; Kwok, John B.; White, Charles L.; Gearing, Marla; Glass, Jonathan; Rollinson, Sara; Pickering-Brown, Stuart; Rohrer, Jonathan D.; Trojanowski, John Q.; Van Deerlin, Vivianna; Bigio, Eileen H.; Troakes, Claire; Al-Sarraj, Safa; Asmann, Yan; Miller, Bruce L.; Graff-Radford, Neill R.; Boeve, Bradley F.; Seeley, William W.; Mackenzie, Ian R. A.; van Swieten, John C.; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa; Neurology, School of Medicine
    Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
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    Pretransplant HLA typing revealed loss of heterozygosity in the major histocompatibility complex in a patient with acute myeloid leukemia
    (Elsevier, 2019) Lobashevsky, Andrew L.; Krueger-Sersen, Mary; Britton, Rebecca M.; Littrell, Courtney A.; Singh, Susmita; Cui, Connie P.; Kashi, Zahra; Martin, Russ K.; Breman, Amy M.; Vance, Gail H.; Farag, Sherif S.; Medicine, School of Medicine
    Introduction Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. Purpose of the study In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. Materials and methods HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. Results Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. Conclusions LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.