AluYb8 insertion polymorphism in the MUTYH gene impairs mitochondrial DNA maintenance and affects the age of onset of IPF

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with an unknown etiology. Increased oxidative stress and mitochondrial dysfunction are thought to be involved in its pathogenesis. However, the effect of the AluYb8MUTYH polymorphism on IPF is not known. Results: The mean age of onset for IPF in patients homozygous for the AluYb8MUTYH variant (P/P) was 66.5 years old, which was significantly earlier than that in patients with the wild-type (A/A, 70.45 years old). For the 97 male IPF patients with lung function data, the FVC% of the P/P patients was lower than that of the wild-type (A/A) or heterozygous (A/P) patients. The laboratory analysis indicated that an increased mtDNA content and impaired mitochondrial quality control were associated with the P/P genotype. We also confirmed that AluYb8 insertion into MUTYH caused decreased MUTYH1 expression in lung tissues. Methods: We compared the lung function of IPF patients and observed the mtDNA content, mtDNA integrity and molecular expression of mitochondrial quality control among subjects with different AluYb8MUTYH genotypes. Additionally, immunoblotting and a reporter gene system were used to test whether altered mitochondrial MUTYH1 expression was linked to AluYb8MUTYH. Conclusions: The AluYb8 insertion polymorphism in MUTYH impairs mtDNA stability and affects the age of onset of IPF.