The European respiratory journal · 2019
A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis.
СтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
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.
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.