Vitamin D-Related Gene Polymorphisms, Plasma 25-Hydroxy-Vitamin D, Cigarette Smoke and Non-Small Cell Lung Cancer (NSCLC) Risk

Abstract

Epidemiological studies regarding the relationship between vitamin D, genetic polymorphisms in the vitamin D metabolism, cigarette smoke and non-small cell lung cancer (NSCLC) risk have not been investigated comprehensively. To search for additional evidence, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and radioimmunoassay method were utilized to evaluate 5 single-nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR), 6 SNPs in 24-hydroxylase (CYP24A1), 2 SNPs in 1α-hydroxylase (CYP27B1) and 2 SNPs in vitamin D-binding protein (group-specific component, GC) and plasma vitamin D levels in 426 NSCLC cases and 445 controls from China. Exposure to cigarette smoke was ascertained through questionnaire information. Multivariable linear regressions and mixed effects models were used in statistical analysis. The results showed that Reference SNP rs6068816 in CYP24A1, rs1544410 and rs731236 in VDR and rs7041 in GC were statistically significant in relation to reduction in NSCLC risk (p < 0.001–0.05). No significant connection was seen between NSCLC risk and overall plasma 25-hydroxyvitamin D [25(OH)D] concentrations, regardless of smoking status. However, the mutation genotype of CYP24A1 rs6068816 and VDR rs1544410 were also significantly associated with increased 25(OH)D levels only in both the smoker and non-smoker cases (p < 0.01–0.05). Meanwhile, smokers and non-smokers with mutated homozygous rs2181874 in CYP24A1 had significantly increased NSCLC risk (odds ratio (OR) = 2.14, 95% confidence interval (CI) 1.47–3.43; p = 0.031; OR = 3.57, 95% CI 2.66–4.74; p = 0.019, respectively). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). However, smokers with mutated homozygous rs6068816 in CYP24A1 had significantly decreased NSCLC risk (OR = 0.43, 95% CI 0.27–1.02; p = 0.006); and smokers and non-smokers with mutated homozygous rs1544410 in VDR had significantly decreased NSCLC risk (OR = 0.51, 95% CI 0.34–1.17; p = 0.002; OR = 0.26, 95% CI 0.20–0.69; p = 0.001, respectively). There are significant joint effects between smoking and CYP24A1 rs2181874, CYP24A1 rs6068816, VDR rs10735810, and VDR rs1544410 (p < 0.01–0.05). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). In summary, the results suggested that the lower the distribution of vitamin D concentration, the more the genetic variations in CYP24A1, VDR and GC genes may be associated with NSCLC risk. In addition, there are significant joint associations of cigarette smoking and vitamin D deficiency on NSCLC risk.

Single Nucleotide Polymorphisms in 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase (CYP27B1) Gene: The Risk of Malignant Tumors and Other Chronic Diseases

“…The two polymorphisms rs10877012 and rs3782130 did not increase the risk of developing this type of cancer. When smokers and non-smokers were compared between themselves, correlating these polymorphisms with the plasma concentration of 25(OH)D did not show any statistical significance [112]. This is consistent with another GWAS, where there was no association between polymorphism in CYP27B1 and level of 25(OH)D [39].…”

Dietary Supplements Commonly Used by Cancer Survivors: Are There Any Benefits?

“…In the second meta‐analysis, Zhang et al observed an RR of 0.83 (95% CI, 0.77–0.90) comparing lowest to highest 25(OH)D levels 43 . Based on circulating 25(OH)D levels, poorer survival and an increased risk for cancer recurrence have been reported by some investigators, while other studies have found no association 44 – 48 …”

Vitamin D Receptor Polymorphism and Cancer: An Update

“…A casecontrol study including 426 patients with non-small cell lung cancer (NSCLC) and 445 controls from China studying VDR polymorphisms rs1544410 and rs731236 found a statistically significant relation between VDR polymorphism and reduction in NSCLC risk (82). Furthermore, the association of increased VDR mRNA expression with worse prognostic factors in papillary thyroid carcinoma suggests the role of VDR in thyroid cancer (83).…”