A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis.

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.

• Authors: 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
• Journal: The European respiratory journal (Eur Respir J) Vol. 53 Issue 6 (06 2019) ISSN: 1399-3003 [Electronic] England
• PMID: 31000673 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2019.

Chemical References

• COUP Transcription Factor II
• NR2F2 protein, human

Topics

• Aged
• Aged, 80 and over
• Base Sequence
• COUP Transcription Factor II (genetics)
• Case-Control Studies
• Female
• Genome-Wide Association Study
• Genotype
• Humans
• Internationality
• Kidney Neoplasms (genetics)
• Logistic Models
• Lung Neoplasms (genetics)
• Lymphangioleiomyomatosis (genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide