Abstract
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.
Abstract
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
Footnotes
This article has supplementary material available from erj.ersjournals.com
Data and code availability: The primary GWAS and replication data will be made available on publication of this work through dbGaP (www.ncbi.nlm.nih.gov/gap).
Author contributions: Contributions to the conception and design of the work: S. Won, E.K. Silverman, G. Hunninghake and D.J. Kwiatkowski. Contributions to the acquisition, analysis or interpretation of data: all authors. Drafting the work or revising it critically for important intellectual content: all authors. Final approval of the version to be published: all authors. Agreement to be accountable for all aspects of the work: all authors.
Conflict of interest: W. Kim has nothing to disclose.
Conflict of interest: K. Giannikou has nothing to disclose.
Conflict of interest: J.R. Dreier has nothing to disclose.
Conflict of interest: S. Lee has nothing to disclose.
Conflict of interest: M.E. Tyburczy has nothing to disclose.
Conflict of interest: E.K. Silverman reports grants from NIH, during the conduct of the study; honoraria for symposium participation from Novartis; and grant and travel support from GlaxoSmithKline, outside the submitted work.
Conflict of interest: E Radzikowska has nothing to disclose.
Conflict of interest: S. Wu has nothing to disclose.
Conflict of interest: C-L. Wu has nothing to disclose.
Conflict of interest: E.P. Henske has nothing to disclose.
Conflict of interest: G. Hunninghake reports personal fees from Genentech, Boehringer Ingelheim, Gerson Lehrman Group and Mitsubishi Chemical, outside the submitted work.
Conflict of interest: H. Carel has nothing to disclose.
Conflict of interest: A. Roman has nothing to disclose.
Conflict of interest: M.A. Pujana reports grants from Roche Pharma outside the submitted work.
Conflict of interest: J. Moss has nothing to disclose.
Conflict of interest: S Won has nothing to disclose.
Conflict of interest: D.J. Kwiatkowski has nothing to disclose.
Support statement: This research was supported by the LAM Foundation, John Adler, The Engles Fund for TSC and LAM research, and the Bio-Synergy Research Project (NRF-2017M3A9C4065964) of the Ministry of Science, ICT and Future Planning through the Korean National Research Foundation and by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 27, 2018.
- Accepted March 19, 2019.
- The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2019
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