{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:54:27Z","timestamp":1789480467287,"version":"build-2803163510"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2017,12,1]],"date-time":"2017-12-01T00:00:00Z","timestamp":1512086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001\u20132013.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score\u2009=\u20093.9), under a recessive disease model with 100% penetrance and a risk allele frequency of 5%. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score\u2009=\u20093.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201612-2479oc","type":"journal-article","created":{"date-parts":[[2017,8,4]],"date-time":"2017-08-04T11:03:18Z","timestamp":1501844598000},"page":"1599-1604","source":"Crossref","is-referenced-by-count":38,"title":["Whole-Exome Sequencing Identifies the 6q12-q16 Linkage Region and a Candidate Gene,\n                    <i>TTK<\/i>\n                    , for Pulmonary Nontuberculous Mycobacterial Disease"],"prefix":"10.1093","volume":"196","author":[{"given":"Fei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva P.","family":"Szymanski","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth N.","family":"Olivier","sequence":"additional","affiliation":[{"name":"Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Tettelin","sequence":"additional","affiliation":[{"name":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Holland","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Duggal","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,12,15]]},"reference":[{"key":"2026032023501818000_bib1","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1164\/rccm.201003-0503OC","article-title":"Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease","volume":"182","author":"Winthrop","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023501818000_bib2","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1086\/648443","article-title":"Nontuberculous mycobacterial disease prevalence and risk factors: a changing epidemiology","volume":"49","author":"Cassidy","year":"2009","journal-title":"Clin Infect Dis"},{"key":"2026032023501818000_bib3","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1164\/rccm.201002-0310OC","article-title":"Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems","volume":"182","author":"Prevots","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023501818000_bib4","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1513\/AnnalsATS.201412-559OC","article-title":"Population-based incidence of pulmonary nontuberculous mycobacterial disease in Oregon 2007 to 2012","volume":"12","author":"Henkle","year":"2015","journal-title":"Ann Am Thorac Soc"},{"key":"2026032023501818000_bib5","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1164\/rccm.200604-571ST","article-title":"An official ATS\/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases","volume":"175","author":"Griffith","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023501818000_bib6","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.3201\/eid1911.130737","article-title":"Pulmonary nontuberculous mycobacterial disease, Ontario, Canada, 1998\u20132010","volume":"19","author":"Marras","year":"2013","journal-title":"Emerg Infect Dis"},{"key":"2026032023501818000_bib7","doi-asserted-by":"crossref","first-page":"e91879","DOI":"10.1371\/journal.pone.0091879","article-title":"Nontuberculous mycobacterial disease mortality in the United States, 1999\u20132010: a population-based comparative study","volume":"9","author":"Mirsaeidi","year":"2014","journal-title":"PLoS One"},{"key":"2026032023501818000_bib8","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1164\/rccm.201111-2016OC","article-title":"Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries","volume":"185","author":"Adjemian","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023501818000_bib9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s12879-016-1521-3","article-title":"Pulmonary Mycobacterium avium-intracellulare is the main driver of the rise in non-tuberculous mycobacteria incidence in England, Wales and Northern Ireland, 2007\u20132012","volume":"16","author":"Shah","year":"2016","journal-title":"BMC Infect Dis"},{"key":"2026032023501818000_bib10","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1136\/thoraxjnl-2013-204260","article-title":"Non-tuberculous mycobacteria: a retrospective review of Scottish isolates from 2000 to 2010","volume":"69","author":"Russell","year":"2014","journal-title":"Thorax"},{"key":"2026032023501818000_bib11","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12879-016-1380-y","article-title":"Increase in non-tuberculous mycobacteria isolated from humans in Tuscany, Italy, from 2004 to 2014","volume":"16","author":"Rindi","year":"2016","journal-title":"BMC Infect Dis"},{"key":"2026032023501818000_bib12","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.3201\/eid2206.151642","article-title":"Prevalence of nontuberculous mycobacterial pulmonary disease, Germany, 2009\u20132014","volume":"22","author":"Ringshausen","year":"2016","journal-title":"Emerg Infect Dis"},{"key":"2026032023501818000_bib13","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/1471-2334-13-231","article-title":"Burden and trends of hospitalisations associated with pulmonary non-tuberculous mycobacterial infections in Germany, 2005\u20132011","volume":"13","author":"Ringshausen","year":"2013","journal-title":"BMC Infect Dis"},{"key":"2026032023501818000_bib14","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.3201\/eid1610.091201","article-title":"Changing epidemiology of pulmonary nontuberculous mycobacteria infections","volume":"16","author":"Thomson","year":"2010","journal-title":"Emerg Infect Dis"},{"key":"2026032023501818000_bib15","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.3201\/eid2206.151086","article-title":"Epidemiology of pulmonary nontuberculous mycobacterial disease, Japan","volume":"22","author":"Namkoong","year":"2016","journal-title":"Emerg Infect Dis"},{"key":"2026032023501818000_bib16","doi-asserted-by":"crossref","first-page":"e0128304","DOI":"10.1371\/journal.pone.0128304","article-title":"Epidemiology and clinical features of pulmonary nontuberculous mycobacteriosis in Nagasaki, Japan","volume":"10","author":"Ide","year":"2015","journal-title":"PLoS One"},{"key":"2026032023501818000_bib17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ccm.2014.10.002","article-title":"Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review","volume":"36","author":"Prevots","year":"2015","journal-title":"Clin Chest Med"},{"key":"2026032023501818000_bib18","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1164\/rccm.200805-686OC","article-title":"Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome","volume":"178","author":"Kim","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023501818000_bib19","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1378\/chest.09-1173","article-title":"Familial clustering of pulmonary nontuberculous mycobacterial disease","volume":"137","author":"Colombo","year":"2010","journal-title":"Chest"},{"key":"2026032023501818000_bib20","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1378\/chest.15-0458","article-title":"Pulmonary disease due to nontuberculous mycobacteria: current state and new insights","volume":"148","author":"McShane","year":"2015","journal-title":"Chest"},{"key":"2026032023501818000_bib21","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1378\/chest.128.1.94","article-title":"NRAMP1 gene polymorphism and susceptibility to nontuberculous mycobacterial lung diseases","volume":"128","author":"Koh","year":"2005","journal-title":"Chest"},{"key":"2026032023501818000_bib22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s00408-009-9136-8","article-title":"HLA antigens and nontuberculous mycobacterial lung disease in Korean patients","volume":"187","author":"Um","year":"2009","journal-title":"Lung"},{"key":"2026032023501818000_bib23","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/jhg.2013.19","article-title":"Association of CFTR gene variants with nontuberculous mycobacterial lung disease in a Korean population with a low prevalence of cystic fibrosis","volume":"58","author":"Jang","year":"2013","journal-title":"J Hum Genet"},{"key":"2026032023501818000_bib24","doi-asserted-by":"crossref","first-page":"e0146585","DOI":"10.1371\/journal.pone.0146585","article-title":"Network analysis of human genes influencing susceptibility to mycobacterial infections","volume":"11","author":"Lipner","year":"2016","journal-title":"PLoS One"},{"key":"2026032023501818000_bib25","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1164\/rccm.201502-0387OC","article-title":"Pulmonary nontuberculous mycobacterial infection: a multisystem, multigenic disease","volume":"192","author":"Szymanski","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023501818000_bib26","author":"Chen"},{"key":"2026032023501818000_bib27","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2026032023501818000_bib28","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/ng786","article-title":"Merlin: rapid analysis of dense genetic maps using sparse gene flow trees","volume":"30","author":"Abecasis","year":"2002","journal-title":"Nat Genet"},{"key":"2026032023501818000_bib29","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1038\/ejhg.2015.64","article-title":"Collapsed haplotype pattern method for linkage analysis of next-generation sequence data","volume":"23","author":"Wang","year":"2015","journal-title":"Eur J Hum Genet"},{"key":"2026032023501818000_bib30","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/gepi.21727","article-title":"Multiple genetic variant association testing by collapsing and kernel methods with pedigree or population structured data","volume":"37","author":"Schaid","year":"2013","journal-title":"Genet Epidemiol"},{"key":"2026032023501818000_bib31","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1086\/424696","article-title":"Guidelines for genotyping in genomewide linkage studies: single-nucleotide-polymorphism maps versus microsatellite maps","volume":"75","author":"Evans","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2026032023501818000_bib32","doi-asserted-by":"crossref","first-page":"5988","DOI":"10.1074\/jbc.M111.307355","article-title":"Characterization of spindle checkpoint kinase Mps1 reveals domain with functional and structural similarities to tetratricopeptide repeat motifs of Bub1 and BubR1 checkpoint kinases","volume":"287","author":"Lee","year":"2012","journal-title":"J Biol Chem"},{"key":"2026032023501818000_bib33","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.cub.2011.12.048","article-title":"CDK-dependent potentiation of MPS1 kinase activity is essential to the mitotic checkpoint","volume":"22","author":"Morin","year":"2012","journal-title":"Curr Biol"},{"key":"2026032023501818000_bib34","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1091\/mbc.02-05-0074","article-title":"Human MPS1 kinase is required for mitotic arrest induced by the loss of CENP-E from kinetochores","volume":"14","author":"Liu","year":"2003","journal-title":"Mol Biol Cell"},{"key":"2026032023501818000_bib35","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.celrep.2015.06.007","article-title":"Plk1 and Mps1 cooperatively regulate the spindle assembly checkpoint in human cells","volume":"12","author":"von Schubert","year":"2015","journal-title":"Cell Reports"},{"key":"2026032023501818000_bib36","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1158\/1535-7163.MCT-13-0324","article-title":"Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715","volume":"13","author":"Slee","year":"2014","journal-title":"Mol Cancer Ther"},{"key":"2026032023501818000_bib37","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1093\/jnci\/djt168","article-title":"Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs","volume":"105","author":"Tannous","year":"2013","journal-title":"J Natl Cancer Inst"},{"key":"2026032023501818000_bib38","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/ng1861","article-title":"A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers","volume":"38","author":"Carter","year":"2006","journal-title":"Nat Genet"},{"key":"2026032023501818000_bib39","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.molcel.2015.11.006","article-title":"Targeting mitosis in cancer: emerging strategies","volume":"60","author":"Dominguez-Brauer","year":"2015","journal-title":"Mol Cell"},{"key":"2026032023501818000_bib40","doi-asserted-by":"crossref","first-page":"7748","DOI":"10.1074\/jbc.M410152200","article-title":"TTK\/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68","volume":"280","author":"Wei","year":"2005","journal-title":"J Biol Chem"},{"key":"2026032023501818000_bib41","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/onc.2008.477","article-title":"The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK\/hMps1","volume":"28","author":"Yeh","year":"2009","journal-title":"Oncogene"},{"key":"2026032023501818000_bib42","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/nar\/gkv1173","article-title":"Requirement for human Mps1\/TTK in oxidative DNA damage repair and cell survival through MDM2 phosphorylation","volume":"44","author":"Yu","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026032023501818000_bib43","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40248-015-0034-z","article-title":"DNA damage and cellular abnormalities in tuberculosis, lung cancer and chronic obstructive pulmonary disease","volume":"10","author":"da Silva","year":"2015","journal-title":"Multidiscip Respir Med"},{"key":"2026032023501818000_bib44","doi-asserted-by":"crossref","first-page":"46120","DOI":"10.18632\/oncotarget.10028","article-title":"Expression of tumor antigens on primary ovarian cancer cells compared to established ovarian cancer cell lines","volume":"7","author":"Kloudov\u00e1","year":"2016","journal-title":"Oncotarget"},{"key":"2026032023501818000_bib45","doi-asserted-by":"crossref","first-page":"503","DOI":"10.3892\/mmr.2015.3412","article-title":"Trophoblast glycoprotein promotes pancreatic ductal adenocarcinoma cell metastasis through Wnt\/planar cell polarity signaling","volume":"12","author":"He","year":"2015","journal-title":"Mol Med Rep"},{"key":"2026032023501818000_bib46","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/bdra.23273","article-title":"Genetic studies of ANKRD6 as a molecular switch between Wnt signaling pathways in human neural tube defects","volume":"103","author":"Allache","year":"2015","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"2026032023501818000_bib47","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/1423-0127-18-66","article-title":"Roles of planar cell polarity pathways in the development of neural [correction of neutral] tube defects","volume":"18","author":"Wu","year":"2011","journal-title":"J Biomed Sci"},{"key":"2026032023501818000_bib48","doi-asserted-by":"crossref","first-page":"D457","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026032023501818000_bib49","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1016\/j.meegid.2011.06.016","article-title":"Genetic variation in IL28RA is associated with the outcomes of HCV infection in a high-risk Chinese population","volume":"11","author":"Cui","year":"2011","journal-title":"Infect Genet Evol"},{"key":"2026032023501818000_bib50","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00430-014-0330-9","article-title":"Interferon \u03bb 1 expression in cervical cells differs between low-risk and high-risk human papillomavirus\u2013positive women","volume":"203","author":"Cannella","year":"2014","journal-title":"Med Microbiol Immunol (Berl)"},{"key":"2026032023501818000_bib51","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1165\/rcmb.2012-0457OC","article-title":"Repression of the equilibrative nucleoside transporters dampens inflammatory lung injury","volume":"49","author":"Morote-Garcia","year":"2013","journal-title":"Am J Respir Cell Mol Biol"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/196\/12\/1599\/67139884\/ajrccm_196_12_1599.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/196\/12\/1599\/67139884\/ajrccm_196_12_1599.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T03:50:52Z","timestamp":1774065052000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/196\/12\/1599\/8499941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,12,15]]},"published-print":{"date-parts":[[2017,12,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201612-2479oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,12]]},"published":{"date-parts":[[2017,12]]}}}