RT Journal Article SR Electronic T1 A Genome-Wide Association Study implicates NR2F2 in Lymphangioleiomyomatosis Pathogenesis JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1900329 DO 10.1183/13993003.00329-2019 A1 Wonji Kim A1 Krinio Giannikou A1 John R. Dreier A1 Sanghun Lee A1 Magdalena E. Tyburczy A1 Edwin K. Silverman A1 Elżbieta Radzikowska A1 Shulin Wu A1 Chin-Lee Wu A1 Elizabeth P. Henske A1 Gary Hunninghake A1 Havi Carel A1 Antonio Roman A1 Miquel Angel Pujana A1 Joel Moss A1 Sungho Won A1 David J. Kwiatkowski YR 2019 UL http://erj.ersjournals.com/content/early/2019/03/15/13993003.00329-2019.abstract AB Rationale Lymphangioleiomyomatosis occurs either associated with Tuberous Sclerosis Complex or as sporadic disease (S-LAM). Risk factors for development of S-LAM are unknown.Objectives 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 SNPs in 426 S-LAM subjects were compared, using conditional logistic regression, to similar data from 852 females from COPDGene in a matched case-control design. For replication studies, genotypes for 196 non-Hispanic white (NHW) female S-LAM subjects were compared with three different sets of controls. RNA-seq and immunohistochemistry analyses were also performed.Results Two non-coding genotyped SNPs met genome-wide significance; rs4544201 and rs2006950 (p-value=4.2×10−8, 6.1×10−9, respectively) which are in the same 35 kb linkage disequilibrium block on chr15q26.2. This association was replicated in an independent cohort. NR2F2, a nuclear receptor and transcription factor, was the only nearby protein-coding gene. NR2F2 expression was higher by RNA-seq in one abdominal LAM tumour and four kidney angiomyolipomas, a LAM-related tumour, compared to all TCGA cancers. Immunohistochemistry showed strong nuclear expression in both LAM and angiomyolipoma tumours.Conclusions SNPs on chr15q26.2 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr Kim has nothing to disclose.Conflict of interest: Dr Giannikou has no conflict of interest.Conflict of interest: Mr Dreier has no conflict of interest.Conflict of interest: Dr Lee has nothing to disclose.Conflict of interest: Dr Tyburczy has no conflict of interest.Conflict of interest: Dr Silverman reports grants from NIH, during the conduct of the study; personal fees from Novartis; and grant and travel support from GlaxoSmithKline, outside the submitted work.Conflict of interest: Dr Radzikowska have no conflict of interest.Conflict of interest: Dr Wu has nothing to disclose.Conflict of interest: Dr Wu has nothing to disclosure.Conflict of interest: Dr Henske has no conflict of interestConflict of interest: Dr Hunninghake reports personal fees from Genentech, personal fees from Boehringer-Ingelheim, personal fees from Gerson Lehrman Group, personal fees from Mitsubishi Chemical, outside the submitted work.Conflict of interest: Dr Carel has nothing to disclose.Conflict of interest: Dr Pujana reports grants from Roche Pharma outside the submitted work.Conflict of interest: Dr Moss has nothing to disclose.Conflict of interest: Dr Kwiatkowski has nothing to disclose.Conflict of interest: Dr Won has nothing to disclose.Conflict of interest: Dr Roman has nothing to disclose.