Vitamin D binding protein gene polymorphisms and the risk of respiratory diseases: a meta-analysis and systematic review

Abstract

Recent studies have found that VDBP gene polymorphism is closely related to the pathogenesis of some respiratory diseases. Rs7041 and rs4588 are two major single-nucleotide polymorphisms(SNPs) in the GC gene encoding VDBP. Different combinations of these variants give rise to three major haplotypic isoforms, GC*1F, GC*1S, and GC*2, which may influence pulmonary immune-inflammatory responses and immune regulation. This systematic review and meta-analysis aimed to clarify the associations between VDBP gene polymorphisms and respiratory diseases including chronic obstructive pulmonary disease(COPD), asthma, Corona Virus Disease-2019(COVID-19) and tuberculosis, so as to provide evidence for the formulation of individualized prevention and therapeutic strategies in the future. We searched the Pubmed, web of science, Wanfang, Embase and China National Knowledge Infrastructure(CNKI) to find the eligible case–control studies. Study quality was assessed using the Newcastle–Ottawa Scale (NOS). Forest plots were generated using Review Manager version 5.4, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A total of 30 studies involving 8,844 participants were included. No significant associations were observed between the rs7041 or rs4588 polymorphism and COPD susceptibility (both P  > 0.05). In the analysis of GC variants, GC*1F-related genetic models were associated with an increased risk of COPD. The ORs for GC*1F/1F versus GC*1F/1S and for GC*1F/1F versus GC*1S/1S group were 1.73 and 2.17, respectively. The OR for the GC*1F/1F homozygous comparison was 1.96, and the GC*1F allele analysis was also statistically significant ( P  = 0.0003). Ethnicity-based subgroup analyses suggested that GC*1F may be primarily associated with increased COPD susceptibility in East Asian populations. In non-East Asian populations, GC*2 showed a trend toward a reduced risk of COPD, although this association did not reach statistical significance (OR = 0.52, P  = 0.09). In the asthma analysis, GC*2 may be associated with an increased risk of asthma ( P  ≤ 0.001). However, because relatively few studies were available for asthma, COVID-19, and tuberculosis, and substantial heterogeneity was present in some analyses, the current evidence remains insufficient to draw definitive conclusions regarding the associations between GC variants and these diseases. The GC*1F allele and GC*1F/1F diplotype may be associated with increased susceptibility to COPD, particularly in East Asian populations, whereas no significant associations were observed between rs7041 or rs4588 and COPD risk. GC*2 may show a potentially protective trend against COPD in non-East Asian populations but may be associated with increased asthma susceptibility. Given the limited and highly heterogeneous evidence regarding asthma, COVID-19, and tuberculosis, further high-quality studies are needed to validate these findings.