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.