The Functional Copy Number Variation-67048 inWWOXContributes to Increased Risk of COPD in Southern and Eastern Chinese

Abstract

Recent studies have recognized the genetic variants in the WW domain-containing oxidoreductase (WWOX) gene as genetic determinants of lung function, reflecting that the WWOX gene may be a susceptible factor of chronic obstructive pulmonary disease (COPD), which characters as poor lung function. We have previously showed that the copy number variation-67048 (CNV-67048) of WWOX was associated with lung cancer risk. Here, we hypothesized that the CNV-67048 affects COPD susceptibility. Based on a two-stage case-control study with a total of 1791 COPD patients and 1940 controls of southern and eastern Chinese, we found that the loss genotypes (0-copy and 1-copy) of CNV-67048 harbored a significantly increased risk of COPD, with an odds ratio (OR) as 1.29 (1.11-1.49) when compared with the common 2-copy genotype. The pre-forced expiratory volume in one second (pre-FEV1) to pre-forced vital capacity (pre-FVC) of carriers with loss genotypes (0.729 ± 0.130) was significantly lower than carriers with 2-copy genotype (0.747 ± 0.124; p = 7.93 × 10(-5)). However, no significant difference was observed on pre-FEV1, pre-FVC and the annual decline of pre-FEV1 between the loss genotypes and 2-copy genotype carriers. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to COPD, which might be a genetic biomarker to predict risk of COPD in Chinese.

Association of nsv823469 copy number loss with decreased risk of chronic obstructive pulmonary disease and pulmonary function in Chinese

“…As of now, only three studies have examined the associations between genomic CNVs and COPD risk42627, and all of them focused on coding genes. In our study, we paid close attention to lncRNA CNVs that are located in the susceptible regions of COPD.…”

WWOX, the FRA16D gene: A target of and a contributor to genomic instability

“…79 It must be noted that CNV-67048 does not correspond to any currently existent nomenclature, however, based on its chromosomal coordinates is the same as esv22307 originally described as a complex variant for both copy number losses but also gains in humans 80 and not just losses as reported in the aforementioned previous studies. [76][77][78][79] It is worth noting that esv22307 lies within the previously described hot spot for germline duplications and deletions within intron 5 of WWOX (Figure 4).…”

“…It was reported that germline variant originally identified as CNV‐67048 of 13.3 Kbp in size mapping to chr16:76929120‐76942453 assembly NCBI36/hg18 (chr16:78337722‐78351055 in GRCh38/hg38) has been linked to the risk of lung cancer, gliomas, ovarian cancer, and also to chronic obstructive pulmonary disease . It must be noted that CNV‐67048 does not correspond to any currently existent nomenclature, however, based on its chromosomal coordinates is the same as esv22307 originally described as a complex variant for both copy number losses but also gains in humans and not just losses as reported in the aforementioned previous studies . It is worth noting that esv22307 lies within the previously described hot spot for germline duplications and deletions within intron 5 of WWOX (Figure ).…”

Rare variant of MAP2K7 is associated with increased risk of COPD in southern and eastern Chinese

“…However, genetic components associated with COPD risk should also be seriously considered for the fact that only a fraction of smokers ever developed COPD . Indeed, a growing number of studies, most prominent of which are the genome‐wide association studies (GWASs), have broadly identified an abundance of genetic variants that are single‐nucleotide polymorphisms (SNPs), to be associated with COPD susceptibility or some phenotypes of COPD …”

“…3 Indeed, a growing number of studies, most prominent of which are the genome-wide association studies (GWASs), have broadly identified an abundance of genetic variants that are single-nucleotide polymorphisms (SNPs), to be associated with COPD susceptibility or some phenotypes of COPD. [4][5][6][7] Despite the unprecedented success achieved in identifying genetic variants associated with COPD risk or lung function, these commonly causal SNPs with minor allele frequency (MAF > 5%) only explained a small fraction of expected heritability of human diseases. 8,9 Common SNPs cannot account for all of the heritability of diseases, thus we still need to make great effort in discovering untapped heritability as a person's susceptibility to disease depends on a combined effect of all disease associated variants.…”