Whole-Exome Sequencing Implicates the USP34 rs777591A > G Intron Variant in Chronic Obstructive Pulmonary Disease in a Kashi Cohort.

Jingran Xu,Aifang Zheng,Ayiguzali Abudukadier,Xiaoguang Zou,Maimaitiaili Tuerxun,Li Li,Dilare Hairoula,Lifeng Tang,Jie Ren,Xuemei Zhong,Sujie Zhang,Chengxin Xie

doi:10.3389/fcell.2021.792027

Jingran Xu, Aifang Zheng + Show 10 more

Open Access

https://doi.org/10.3389/fcell.2021.792027

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Abstract

Genetic factors are important factors in chronic obstructive pulmonary disease (COPD) onset. Plenty of risk and new causative genes for COPD have been identified in patients of the Chinese Han population. In contrast, we know considerably little concerning the genetics in the Kashi COPD population (Uyghur). This study aims at clarifying the genetic maps regarding COPD susceptibility in Kashi (China). Whole-exome sequencing (WES) was used to analyze three Uyghur families with COPD in Kashi (eight patients and one healthy control). Sanger sequencing was also used to verify the WES results in 541 unrelated Uyghur COPD patients and 534 Uyghur healthy controls. WES showed 72 single nucleotide variants (SNVs), two deletions, and small insertions (InDels), 26 copy number variants (CNVs), and 34 structural variants (SVs), including g.71230620T > A (rs12449210T > A, NC_000,016.10) in the HYDIN axonemal central pair apparatus protein (HYDIN) gene and g.61190482A > G (rs777591A > G, NC_000002.12) in the ubiquitin-specific protease 34 (USP34) gene. After Sanger sequencing, we found that rs777591“AA” under different genetic models except for the dominant model (adjusted OR = 0.8559, 95%CI 0.6568–1.115, p > .05), could significantly reduce COPD risk, but rs12449210T > A was not related to COPD. In stratified analysis of smoking status, rs777591“AA” reduced COPD risk significantly among the nonsmoker group. Protein and mRNA expression of USP34 in cigarette smoke extract-treated BEAS-2b cells increased significantly compared with those in the control group. Our findings associate the USP34 rs777591“AA” genotype as a protector factor in COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a common and complicated disease of the lungs
We found that “AA” in rs777591A > G was a protective factor against COPD, whereas rs12449210T > A was not related to COPD susceptibility in Kashi COPD population. mRNA and protein expression of ubiquitin-specific protease 34 (USP34) and Iκbα were obviously increased in CSEtreated BEAS-2b cells in vitro study
HYDIN might be related to the abnormal function of respiratory-tract mucosal cilia in COPD, but we showed in a case-control study that HYDIN had little effect on the occurrence and development of COPD

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a common and complicated disease of the lungs. It is characterized by continuous and irreversible airflow destruction due to chronic inflammation (Lozano et al, 2012). Our epidemiological investigation shows the COPD prevalence in Kashi (Xinjiang, China) to be 17.01% (Li et al, 2021), which is higher than that in other parts of China. COPD development rs777591A > G in USP34 by WES involves environmental factors (e.g., smoking, air pollution), genetic susceptibility, and infection (Zhang et al, 2014). Scholars have found that some genes might be related to COPD genetic susceptibility of the Chinese Han population (Wang C. et al, 2018; Zhang et al, 2020). The study for COPD is still lacking in Kashi

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