A Genome-Wide Association Study implicates NR2F2 in Lymphangioleiomyomatosis Pathogenesis

Rationale Lymphangioleiomyomatosis occurs either associated with Tuberous Sclerosis Complex or as sporadic disease (S-LAM). Risk factors for development of S-LAM are unknown. Objectives 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 SNPs in 426 S-LAM subjects were compared, using conditional logistic regression, to similar data from 852 females from COPDGene in a matched case-control design. For replication studies, genotypes for 196 non-Hispanic white (NHW) female S-LAM subjects were compared with three different sets of controls. RNA-seq and immunohistochemistry analyses were also performed. Results Two non-coding genotyped SNPs met genome-wide significance; rs4544201 and rs2006950 (p-value=4.2×10 −8 , 6.1×10 −9 , respectively) which are in the same 35 kb linkage disequilibrium block on chr15q26.2. This association was replicated in an independent cohort. NR2F2 , a nuclear receptor and transcription factor, was the only nearby protein-coding gene. NR2F2 expression was higher by RNA-seq in one abdominal LAM tumour and four kidney angiomyolipomas, a LAM-related tumour, compared to all TCGA cancers. Immunohistochemistry showed strong nuclear expression in both LAM and angiomyolipoma tumours. Conclusions SNPs on chr15q26.2 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.