Revealing the association between vitamin D metabolic pathway gene variants and lung cancer risk: a systematic review and meta-analysis

Abstract

Lung cancer is a crucial global issue, with more than one million deaths annually. While smoking is considered the main etiology of the disease, several genetic variants are associated with it. Alterations in vitamin D pathway genes have also been studied in regards to lung cancer, but the findings have been inconclusive. We here present a systematic review and meta-analysis of seven genes in this pathway: <i>CYP2R1</i>, <i>CYP27B1</i>, <i>CYP24A1</i>, <i>CYP3A4</i>, <i>CYP3A5</i>, <i>GC</i>, and <i>VDR</i>. Four databases (PubMed, Scopus, Cochrane Library, and Web of Science (WOS) databases) were searched. From these, 16 eligible case-control studies comprising 6,206 lung cancer cases and 7,272 health controls were obtained. These studies were subjected to comprehensive data extraction and quality scoring, and the pooled odds ratio with a 95% confidence interval was calculated to estimate the effect of each variant along with heterogeneity analysis and a risk of bias assessment. Our meta-analysis revealed an association between <i>CYP3A4</i> (rs2740574) and lung cancer in the allelic, heterozygous, and dominant models. In addition, both <i>VDR</i> (Fok1: rs2228570) and <i>VDR</i> (Cdx-2: rs11568820) displayed a protective role in lung cancer development in the heterozygous and dominant models. Furthermore, <i>VDR</i> (Taq1: rs731236) showed a decreased risk of lung cancer in the allelic, homozygous, and recessive models. Similarly, <i>VDR</i> (BsmI: rs1544410) had a positive effect on lung cancer risk when subjected to allelic and recessive models. Our meta-analysis revealed the lack of association of <i>CYP2R1</i> (rs10741657), <i>CYP27B1</i> (rs3782130), <i>CYP27B1</i> (rs10877012), <i>CYP24A1</i> (rs6068816), <i>CYP24A1</i> (rs4809960), <i>CYP3A5</i> (rs776746), <i>GC</i> (rs7041), <i>GC</i> (rs4588), and <i>VDR</i> (ApaI: rs7975232) with lung cancer. Our work revealed that <i>CYP3A4</i> (rs2740574) can represent an independent risk factor for lung cancer. This conclusion can aid better personalized medicine for lung cancer management, while further assessment for genetic variants of <i>CYP3A4</i>, <i>CYP27B1</i>, <i>CYP24A1</i>, <i>GC</i>, and <i>VDR</i> is still required to address more robust evidence.