Chronic obstructive pulmonary disease (COPD) is a multifactorial chronic respiratory disease characterized by irreversible pulmonary airflow obstruction.1,2 Many studies have shown that the development of COPD is influenced by environmental factors and a complex set of genetic traits.2–4 Recently, genome-wide association and exome sequencing studies have been used to identify the hereditary factors of COPD among different populations, but the effect of genetic variants on COPD is still unclear.5

Micro RNAs (miRNAs) are a class of endogenous non-coding RNAs, 22–25 nucleotides in length that can bind to the 3′-UTR region of mRNA transcripts, thereby inhibiting their translation and expression.6,7 Variants in miRNAs are thought to be involved in post-transcriptional regulation and influence disease susceptibility.7,8 Zhou et al and Wang et al found that the miR-146a rs2910164 single nucleotide polymorphism (SNP) is associated with improved lung function in smokers with COPD.7,8 Related studies in the Korean population have suggested that gene polymorphisms in miR-196a2, miR-146a, and miR-499 could be associated with asthma phenotypes.6 Fawzy et al also found a significant association between the miR-196a2 rs11614913 polymorphism and the bronchodilator response in Egyptians with COPD.9 Therefore, it is important to explore the effect of miRNA variants on susceptibility to COPD.

MIR5708 and MIR1208 are miRNAs located on chromosome 8. MIR5708 has been identified as a risk locus for rheumatoid arthritis through gene-based association testing.10MIR1208 is thought to be involved in the regulation of tumor-related pathways by binding to the upstream gene circMTUS1.11 Relevant studies have also recognized MIR1208 as a tumor suppressor gene that can increase sensitivity of renal cancer cells to cisplatin.12 Moreover, genetic polymorphisms of MIR1208 rs2648841 have been found to be related to chemotherapy toxicity in children with acute lymphoblastic leukemia.13 However, to the best of our knowledge, the influence of MIR5708 and MIR1208 polymorphisms on the risk of COPD has not been studied.

Therefore, we performed this case-control study to investigate the relationship between MIR5708 (rs6473227 and rs16907751) and MIR1208 (rs2608029 and rs13280095) polymorphisms and susceptibility of Chinese to COPD, and to explain the roles of genetic factors in the pathogenesis of COPD through statistical analysis.

According to the latest Global Health Observatory data, COPD was ranked as the third leading cause of death worldwide, accounting for approximately 5% of all deaths globally in 2015 (3.17 million deaths). The prevalence and burden of COPD are projected to increase over the coming decades.15 It has been clearly demonstrated that the interaction between genotype and environment plays an important role in COPD phenotypes.16,17 Genetic background plays a critical role in the development of COPD, and related studies have proposed significant differences in genetic susceptibility to COPD among different races and ethnicities.18 Therefore, the effect of genetic polymorphisms of candidate genes on the risk of COPD among Chinese was examined.

As a result, statistical analysis of the genotyping results of 315 COPD patients and 314 healthy controls among Chinese patients identified MIR5708 rs16907751 as a risk factor of COPD, and significant associations between rs16907751 and clinical indexes including PR and FEV1 in COPD patients were found. The examined mutation loci have been rarely reported; only rs6473227 showed a close relationship with atopic dermatitis in a related case-control analysis.19 Our results suggest that rs6473227 may contribute to an increased risk of COPD in individuals with a BMI less than 24. A related study pointed out that neuroimmune interactions are implicated in chronic inflammations such as atopic dermatitis, COPD, and asthma20; therefore, we hypothesized that MIR5708 rs6473227 may increase susceptibility to inflammation-related disorders. In addition, we found that MIR5708 rs16907751 may increase the risk of COPD in patients with normal BMI. There have been studies supporting our findings and reported that low BMI is a risk factor for accelerated decline in lung function compared to normal BMI,21 thereby suggesting a protective role of high BMI in COPD patients.

Tobacco smoking is widely recognized as the most important risk factor for COPD,22 but it is not the only risk factor for COPD. Qian et al. concluded that both non-smokers and smokers are likely to suffer from COPD, which may be the result of differential miRNA expression between.23 At present, there has been no report on the association between miR5708 and miR1208 and the risk of disease COPD. However, our study further provided evidence that allele T of MIR5708 rs16907751 may increase susceptibility of nonsmokers to COPD. There have been reports confirming that up to 30% of patients with COPD do not have a smoking history.18 Therefore, multiple genes and exposure to environmental and occupational factors are thought to jointly affect COPD development.

Furthermore, we also found that the effects of MIR5708 and MIR1208 on the risk of COPD were age- and sex-dependent. Related epidemiological studies have shown that the prevalence of COPD increases with age,24 and Mercado et al. also showed that aging of the lung resulted in loss of lung elasticity and reduced ability to respond to environmental stress and damage.25 Our findings also indicated MIR5708 rs16907751 as a risk factor for COPD in patients over 70 years of age. Based on the stratified analysis, our results suggested that MIR5708 rs16907751 and MIR1208 rs2608029 are associated with increased COPD risk in men and women, respectively, and further confirmed gender differences in COPD susceptibility conferred by these two SNPs. Aryal et al. stated that the differences in sex were derived mainly by smoking status, hormone levels, and behavioral differences.26 Current data indicate that in China, the prevalence of COPD in men is higher than that in women, but the difference varies with exposure to risk factors and socioeconomic development in different geographic regions.27,28 However, in our current study, we did not focus on the effect of environment, occupational differences, and regional constraints. Moreover, the small sample size and incomplete sample information in some cases are also limitations of our study. Subsequent functional experiments are needed to verify the effects of these SNPs on COPD.

In summary, this study is the first to indicate that genetic variants in MIR5708 and MIR1208 are associated with an increased risk of COPD in the Chinese population, and the effects of these SNPs are related to age, sex, smoking status, and BMI.