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 VO 53 IS 6 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/53/6/1900329.abstract AB 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.GWAS identified alleles of two SNPs near NR2F2 that were associated with sporadic lymphangioleiomyomatosis. NR2F2 is a transcription factor that is expressed highly in both LAM and a LAM-related tumour, and NR2F2 is a new LAM gene. http://ow.ly/87xx30oiVhZ