Chronic obstructive pulmonary disease (COPD) is a common and currently treatable but incurable disease. The World Health Organization estimates that COPD will be the third leading cause of death globally by 2030, but that prediction has already come true ahead of time, causing 3.23 million global deaths in 2019, with a significant social and economic burden (1). The disease is a progressive disorder characterized by persistent airflow restriction due to structural changes and chronic inflammation (2). Patients with COPD experience a progressive decline in lung function, a decreased capacity for exercise, frequent disease exasperations, and the progress of extrapulmonary comorbidities such as cardiovascular disease, osteoporosis, and infections (3). COPD poses a serious threat to the lives and health of patients. In addition, it also makes a huge economic burden on society and families because of the high cost of treatment despite great progress has been made in understanding its pathogenesis, natural history, and management, there still exist many open questions, especially concerning how to exactly control the risk factors.

25-Hydroxyvitamin D (25OHD) can best reflect human vitamin D status. A correlation has been demonstrated between 25OHD levels and the status of lung function, including COPD. For example, an age-matched controlled study reported that the patients in the COPD group had significantly lower vitamin D levels than those without the COPD group, suggesting that COPD patients have a higher vitamin D deficiency risk (4, 5). Jorde et al. (6) in a cross-sectional observational study found that there was a fair correlation between serum 25OHD and the current FEV1. Vitamin D-deficient patients had a greater FEV1 decrease than the others in the Norway cohort (7). A prospective cohort study reported an association of lower plasma 25OHD levels with lower lung function, a faster decline in lung function, and a higher risk of COPD (8). At present, the mechanism of how vitamin D reduces the risk of COPD is not clear. Some researchers have attempted to explain their relationship in terms of various immunomodulatory effects and airway smooth muscle remodeling (9). However, most of the current reports are based on observational studies, which are vulnerable to reverse associations, confounding factors, or limited sample sizes.

Mendelian randomization (MR) is a genetic instrumental variable analysis in which observational data can be applied to reconfirm the correlation between genetically predicted exposure (25 OHD) and outcome (COPD) by using genetic variation associated with different levels of modifiable risk factors to assess the impact of risk factors on disease. Furthermore, MR study designs are less susceptible to confounding and reverse bias than observational studies because genetic variation will not be affected by disease state or other risks (10).

Building on the previous genome-wide association study (GWAS), which was finished based on real detected 25OHD levels, we predicted the 25OHD levels based on our selected significant SNP loci. And then, the relationship between genetically predicted 25OHD levels and COPD was further explored by using a two-sample MR analysis in the present study.

Our study assessed the potential role of vitamin D levels on COPD risk by using a new genetic tool (two-sample MR design). The results showed that the COPD risk decreased as genetically predicted 25OHD levels increased, suggesting that vitamin D levels may play a key role in the occurrence and development of COPD.

Recently, there have been growing studies exploring the potential noncalcifying role of vitamin D and the association between vitamin D and chronic diseases, especially COPD. In prior researches, the correlation between vitamin D and the risk of COPD has been explored. Many observational studies have reported the complex correlations among the serum 25-OHD levels, systemic inflammation, disease severity, and progression (6, 7, 27). A prospective cohort study with 10,116 participants from the Copenhagen City Heart Study and 8,391 participants from the Copenhagen General Population Study also reported a correlation between lower plasma 25OHD levels with lower lung function, a faster decline in lung function, and a higher risk of COPD (HR: 1.58, 95% CI: 1.05–2.40 and HR: 2.00, 95% CI: 1.19–3.36 for the two studies, respectively) (8). In the present study, we found a reverse relationship between genetically predicted 25OHD and COPD, with the relative risk of COPD decreasing with genetically predicted increasing 25OHD concentrations, which is consistent with previous observational findings. Even though we used the significant SNPs rather than the actual measured serum 25OHD levels, we can explore the association, rather than the observational association due to that these SNPs have been randomly assigned to the offspring before the disease occurred and few confounders can bias the conclusion of MR analysis, which is the most significant strength of MR analysis.

In the present MR, we only explored the association between genetically predicted increasing 25OHD concentrations and COPD risk. Therefore, whether patients with COPD may benefit from the supplementation with vitamin D cannot be further analyzed in our study. However, some other research found that timely supplementation with vitamin D can delay the course of COPD patients and improve their lung function. For example, Lehouck et al. (28) reported that 30 participants with severe vitamin D deficiency at baseline (serum 25OHD level of 10 ng/ml) showed a significant reduction in exacerbations in patients with a timely supplementation of vitamin D compared to the placebo group. Besides, Martineau et al. (29) also indicated that the relationship between vitamin D deficiency in COPD patients reduced the risk of moderate or severe exacerbations.

Multiple mechanisms may contribute to the relationship between vitamin D and COPD. First, animal studies showed that vitamin D had positive effects on fibroblast proliferation, alveolar type II cells, alveolarization, and surfactant synthesis, and it may improve the lung function of patients and reduce the risk of CPOD (30). Second, immunological studies found evidence for Th1 immunity and Th17 involvement in COPD (5). For example, vitamin D deficiency may enhance inflammation, chemokine production via NF-ƘB, parenchymal degradation, TNF-α, IL-18, histone acetylation, corticosteroid resistance, and matrix metalloproteinase (MMP)-9 production. Third, vitamin D also plays a role in remodeling airway smooth muscle to regulate lung function in COPD (31). Besides, increasing 25OHD concentrations in COPD patients to the optimal range may reduce accompanying exacerbations and bacterial load (32–37).

Ahn et al. (38) reported a significant relationship between rs3829251 and 25OHD (p = 8.8 × 10⁻⁷), and our colocalization analyses inferred that rs3829251, which is located in the 7-dehydrocholesterol reductase gene, might impact the concentration of human 25OHD by regulating the expression of NADSYN1/DHCR7, consequently reducing COPD risk. However, how the rs3829251 locus affects the occurrence of COPD by impacting 25OHD is currently unclear. Thus, more research is needed in the future.

A strength of this study is that we used an MR design to explore the relationship between vitamin D and the COPD risk by using summary data from the largest GWAS studies, which can minimize the residual confounding and possibly reversed bias compared to previous observational studies. Furthermore, we further validate our results by applying other approaches, such as MR-PARS, MR-PRESSO and maximum likelihood, and the consistency of the results makes our results more robust. In addition, we also adopted colocalization analyses and MR Steiger approaches to make our results more reliable.

However, some limitations in this two-sample MR study should be noted. First, the GWAS dataset used in this study is based on a population of European ancestry, and it is unclear whether the results apply to people of non-European ancestry. Second, we cannot completely rule out the possible interactions of gene–environment or diet–gene that influenced our results. In addition, it is difficult for us to evaluate whether Vitamin D supplementation influenced the rate of moderate or severe COPD exacerbations due to the original GWAS involving all the patients, including both moderate and severe COPD exacerbations. Finally, sensitivity analyses such as weighted median, MR–Egger, MR-PRESSO, etc., were used to test and correct the potential horizontal pleiotropy; however, we were unable to address the issue of unobserved pleiotropy, which may affect the conclusion of evaluating the association between genetically predicted vitamin D and the risk of COPD.

Our study showed that vitamin D levels may be negatively associated with COPD risk. Further studies are needed to elucidate the underlying mechanism.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number (s) can be found in the article/Supplementary material.

KL and J-ST designed the study and wrote the manuscript. KL, J-ST, T-QL, JY, and HW contributed to the data analysis and data interpretation. WW contributed to the revision of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China Grant Awards (grant number 81960669) and the science and technology project of Guozhong Healthcare (grant number GGH-SDEPCH-HP-20230101).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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