Genomic Loci of Radiation-induced Lung Disease in a Mouse Model: Refinement and Candidate Gene Analysis.

Abstract

Susceptibility to radiation-induced lung disease differs among people and among inbred strains of mice; C3H/HeJ mice develop early onset distress from pneumonitis and C57BL/6J mice present later onset pneumonitis with fibrosis. Previous studies revealed C3H/HeJ alleles at a 28 Mb locus on chromosome 2 to be linked to early onset distress and at an 18 Mb locus on chromosome 17 (called Radpf1 for radiation-induced pulmonary fibrosis-1) to decrease fibrosis in whole-thorax irradiated mice. To potentially reduce these genomic intervals, parental chr17-subcongenic mice with 0.71 Mb of C3H/HeJ alleles, and chr 2-congenic mice with region-spanning C3H/HeJ alleles from 95 to 123 Mb, and four lines of subcongenic mice received 16 Gy whole thorax irradiation and were assessed for onset of respiratory distress and histological lung disease at distress. One hundred percent of irradiated C3H/HeJ and C57BL/6J mice exhibited respiratory distress from pneumonitis and pneumonitis with fibrosis (6.8% of lung), respectively, while 18/19 chr17-subcongenic mice survived to 25 weeks post-treatment without symptoms of distress and with significantly decreased radiation-induced pulmonary fibrosis (0.3% of lung, P = 0.002). Of the chr2-subcongenics, mice of one line, which we refer to as Pneum1 (pneumonitis one), succumbed at an average of 20.2 ± 1.1 weeks postirradiation in females and 26.3 ± 1.2 weeks in males (P > 0.22 vs. congenic mice), reducing this locus to 5.6 Mb. Bioinformatic analyses revealed 114 candidate genes within these reduced intervals, with effects on pathways including on immune pathways. Mapping refined genetic susceptibility to radiation-induced lung disease in mice.