한빛사 논문
Wonji Kim1,2,13, Krinio Giannikou3,13, John R. Dreier3, Sanghun Lee4, Magdalena E. Tyburczy3, Edwin K. Silverman2,3, Elżbieta Radzikowska5, Shulin Wu6, Chin-Lee Wu6, Elizabeth P. Henske3, Gary Hunninghake3, Havi Carel7, Antonio Roman8, Miquel Angel Pujana9, Joel Moss10, Sungho Won11,12,14 and David J. Kwiatkowski3,14
1Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, Korea. 2Channing Division of Network Medicine, Dept of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. 3Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. 4Dept of Medical Consilience, Graduate School, Dankook University, Yongin-si, Korea. 5National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland. 6Urology Research Laboratory, Massachusetts General Hospital, Boston, MA, USA. 7Dept of Philosophy, University of Bristol, Bristol, UK. 8Vall d’Hebron University Hospital, CIBERES, Barcelona, Spain. 9ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain. 10Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 11Dept of Public Health Sciences, Seoul National University, Seoul, Korea. 12Institute of Health and Environment, Seoul National University, Seoul, Korea. 13These two authors contributed equally to this work. 14Joint senior authors.
Correspondence: David J. Kwiatkowski, Division of Pulmonary Medicine, Brigham and Women’s Hospital, 20 Shattuck Street, Boston, MA 02115, USA.
Abstract
Introduction : Lymphangioleiomyomatosis (LAM) occurs either associated with tuberous sclerosis complex (TSC) or as sporadic disease (S-LAM). Risk factors for development of S-LAM are unknown. We hypothesised that DNA sequence variants outside of TSC2/TSC1 might be associated with susceptibility for S-LAM and performed a genome-wide association study (GWAS).
Methods : Genotyped and imputed data on 5 426 936 single nucleotide polymorphisms (SNPs) in 426 S-LAM subjects were compared, using conditional logistic regression, with similar data from 852 females from COPDGene in a matched case–control design. For replication studies, genotypes for 196 non-Hispanic White female S-LAM subjects were compared with three different sets of controls. RNA sequencing and immunohistochemistry analyses were also performed.
Results : Two noncoding genotyped SNPs met genome-wide significance: rs4544201 and rs2006950 (p=4.2×10−8 and 6.1×10−9, respectively), which are in the same 35 kb linkage disequilibrium block on chromosome 15q26.2. This association was replicated in an independent cohort. NR2F2 (nuclear receptor subfamily 2 group F member 2), a nuclear receptor and transcription factor, was the only nearby protein-coding gene. NR2F2 expression was higher by RNA sequencing in one abdominal LAM tumour and four kidney angiomyolipomas, a LAM-related tumour, compared with all cancers from The Cancer Genome Atlas. Immunohistochemistry showed strong nuclear expression in both LAM and angiomyolipoma tumours.
Conclusions : SNPs on chromosome 15q26.2 are associated with S-LAM, and chromatin and expression data suggest that this association may occur through effects on NR2F2 expression, which potentially plays an important role in S-LAM development.
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