A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis
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 / might be associated with susceptibility for S-LAM and performed a g...
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Published in | The European respiratory journal Vol. 53; no. 6; p. 1900329 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.06.2019
|
Online Access | Get full text |
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Summary: | 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
/
might be associated with susceptibility for S-LAM and performed a genome-wide association study (GWAS).
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.
Two noncoding genotyped SNPs met genome-wide significance: rs4544201 and rs2006950 (p=4.2×10
and 6.1×10
, respectively), which are in the same 35 kb linkage disequilibrium block on chromosome 15q26.2. This association was replicated in an independent cohort.
(nuclear receptor subfamily 2 group F member 2), a nuclear receptor and transcription factor, was the only nearby protein-coding gene.
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.
SNPs on chromosome 15q26.2 are associated with S-LAM, and chromatin and expression data suggest that this association may occur through effects on
expression, which potentially plays an important role in S-LAM development. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0903-1936 1399-3003 |
DOI: | 10.1183/13993003.00329-2019 |