A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis

Wonji Kim, Krinio Giannikou, John R. Dreier, Sanghun Lee, Magdalena E. Tyburczy, Edwin K. Silverman, Elżbieta Radzikowska, Shulin Wu, Chin Lee Wu, Elizabeth P. Henske, Gary Hunninghake, Havi Carel, Antonio Roman, Miquel Angel Pujana, Joel Moss, Sungho Won, David J. Kwiatkowski

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)


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.

Original languageEnglish
JournalThe European respiratory journal
Issue number6
Publication statusPublished - 27 Jun 2019

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