A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis

• Published in: The European respiratory journal Vol. 53; no. 6; p. 1900329
• Main Authors: Kim, Wonji, Giannikou, Krinio, Dreier, John R, Lee, Sanghun, Tyburczy, Magdalena E, Silverman, Edwin K, Radzikowska, Elżbieta, Wu, Shulin, Wu, Chin-Lee, Henske, Elizabeth P, Hunninghake, Gary, Carel, Havi, Roman, Antonio, Pujana, Miquel Angel, Moss, Joel, Won, Sungho, Kwiatkowski, David J
• Format: Journal Article
• Language: English
• Published: England 01.06.2019
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/13993003.00329-2019

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.