Mizanur Rahman, PhD

(He/Him/His)

Rank

Fellow or Postdoc

Department

Medicine

Pulmonary and Critical care

Authors

Mizanur Rahman, Peter J. Castaldi, Aabida Saferali, Congjian Liu, Xiaobo Zhou, Craig P. Hersh, Robert P. Chase, Zhonghui Xu, Zerihun Negasi, Kamakshi Bankoti, Michael Cho, Yohannes Tesfaigzi

Principal Investigator

Yohannes Tesfaigzi

Twitter / Website

Categories

Importance of MUTYH in Chronic Obstructive Pulmonary Disease Discovered by Genome-wide Association Studies and Quantitative Traits in Airway Epithelia

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Abstract

Genome-wide association studies (GWAS) revealed over eighty genetic regions associated with chronic obstructive pulmonary disease (COPD), but their functions remain elusive. The present study aimed to identify COPD-causing genes in the COPD GWAS-identified locus near the base excision repair gene, MUTYH.
Genome-wide genotyping and bulk RNA sequencing of human airway epithelial cells (HAECs) from 185 individuals revealed colocalization between the GWAS and eQTL signals near the MUTYH locus. Expression of MUTYH was reduced in AECs homozygous for the COPD risk allele GG in the colocalized SNP, rs2356553. Treatment with H2O2 or cigarette smoke (CS) caused higher levels of 8-oxo-dG formation in HAEC with GG genotype (HAECGG – low MUTYH) compared with the CC genotype (HAECCC high MUTYH). A similar effect was observed in isogenic in HAECCC cultures when MUTYH was suppressed using siRNA. CS treatment decreased MUTYH protein levels in HAECs with both genotypes, but the levels recovered over 72 h in HAECCC but not in HAECGG cultures were maintained in media without CS. Over several passages, CS-treated HAECGG cultures underwent senescence earlier and expressed higher levels of p53 (a marker of senescence) compared with the HAECGG cultures. Similarly, exposure of mice over 6 months decreased MUTYH and increased 8-oxo-dG levels in mouse airway epithelia, and MUTYH levels recovered when mice were kept in air for an additional 6 months. In former smokers with COPD compared with non-COPD matched for age, sex, and body mass index, MUTYH levels were reduced, and 8-oxo-dG were increased in airway epithelia. These findings suggest that impaired DNA damage repair in former smokers with the GG genotype triggers senescence in airway epithelia that potentially contributes to COPD development.