TY - T1的全基因组关联研究小鬼licates NR2F2 in lymphangioleiomyomatosis pathogenesis JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00329-2019 VL - 53 IS - 6 SP - 1900329 AU - Kim, Wonji AU - Giannikou, Krinio AU - Dreier, John R. AU - Lee, Sanghun AU - Tyburczy, Magdalena E. AU - Silverman, Edwin K. AU - Radzikowska, Elżbieta AU - Wu, Shulin AU - Wu, Chin-Lee AU - Henske, Elizabeth P. AU - Hunninghake, Gary AU - Carel, Havi AU - Roman, Antonio AU - Pujana, Miquel Angel AU - Moss, Joel AU - Won, Sungho AU - Kwiatkowski, David J. Y1 - 2019/06/01 UR - //www.qdcxjkg.com/content/53/6/1900329.abstract N2 - 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 ER -