Vitamin D Gene Variants Fail to Explain Bladder Cancer Risk in Turkish Study

Bladder cancer remains one of the most common malignant tumors of the urinary system and a stubborn public health challenge worldwide, yet the reasons why some people develop the disease while others do not are still only partly understood. Smoking and occupational chemical exposures explain a large share of cases, but they do not explain everything. Genetic variation is thought to shape individual susceptibility, and one biological pathway that has attracted growing attention is vitamin D metabolism. A new case-control study from Turkey, published in Molecular Biology Reports, has now tested whether two common variants in a key vitamin D-metabolizing gene, CYP24A1, influence the odds of developing bladder cancer in a Caucasian population for the first time. The answer, according to the data, is a cautious no.

The research team, led by Hasan Sulhan of Adıyaman University together with Yakup Akkoç of Ardahan University and Ersin Akgöllü of Ağrı İbrahim Çeçen University, focused on two single nucleotide polymorphisms, or SNPs, known as rs1570669 and rs2762934. SNPs are the most common form of human genetic variation, involving a change of a single DNA letter at a specific position in the genome. Most SNPs are harmless, but some can subtly alter how genes are expressed or how their proteins function, and in doing so they can shift disease risk by small but measurable amounts. Because such effects are individually modest, detecting them requires carefully matched groups of patients and healthy controls, which is precisely the design the Turkish team adopted.

The choice of the CYP24A1 gene was not arbitrary. This gene encodes 24-hydroxylase, the mitochondrial enzyme responsible for degrading active vitamin D metabolites. When vitamin D is converted into its active hormonal form, calcitriol, the body must eventually break it down to prevent calcium levels from rising dangerously. CYP24A1 performs that catabolic step, converting active metabolites into water-soluble forms that can be excreted. But the enzyme has a second, more sinister role in cancer biology. In many tumors, including bladder tumors, CYP24A1 is overexpressed, which depletes the local supply of calcitriol. This matters because vitamin D signaling has been linked to cell differentiation, growth inhibition, and tumor suppression in numerous studies, and low blood levels of 25-hydroxyvitamin D have been associated with increased bladder cancer risk in systematic reviews. In other words, a gene variant that changes how efficiently CYP24A1 works could, in principle, change how much protective vitamin D signaling is available inside the bladder tissue.

Both variants examined in the study sit in regulatory regions of the CYP24A1 gene rather than in its protein-coding sequence. The rs1570669 variant lies in the promoter region, the stretch of DNA upstream of the gene that controls how actively it is transcribed, while rs2762934 is located in an intron, an intervening sequence whose variants can influence gene expression or splicing through regulatory mechanisms. Previous research had hinted at relevance to cancer. A 2020 study in Public Health Genomics reported that the rs1570669 variant had a protective effect against tumors of the urinary system, and a 2025 study in Biochem Genetics examined the association between CYP24A1 polymorphisms and bladder cancer risk in the Chinese Han population. What was missing, the Turkish authors noted, was any evidence from a Caucasian cohort, since allele frequencies and genetic backgrounds can differ substantially between populations. Their study therefore represents the first attempt to evaluate these two variants in relation to bladder cancer susceptibility in a Turkish population.

To do so, the researchers enrolled 152 patients with bladder cancer and 178 healthy controls, genotyping both groups using a TaqMan allelic discrimination assay performed with real-time quantitative PCR. This technique uses fluorescent probes that bind specifically to one allele or the other, allowing each participant’s genotype to be read out from the pattern of fluorescence emitted as the DNA is amplified. It is a fast, reliable, and widely used method for SNP genotyping in clinical research. The team also collected clinical and demographic information, including age, body mass index, smoking status, and vitamin D levels, so that the genetic comparisons could be interpreted in context and potential confounders could be identified.

The headline result was negative. Neither rs1570669 nor rs2762934 showed a statistically significant association with bladder cancer risk in this cohort. Carrying one or two copies of a particular allele at either variant did not meaningfully change the odds of being a bladder cancer patient rather than a control once the data were analyzed. However, the authors observed something that kept the story from being entirely closed: the A alleles of both variants showed a non-significant trend toward increased odds of bladder cancer. In genetic association studies, such trends are exactly the kind of signal that can either evaporate in larger samples or harden into a real effect, and the authors explicitly suggest that further investigation in larger cohorts may be warranted before the question is settled.

The comparison between patients and controls also revealed significant differences in age, body mass index, and smoking status, three well-established risk factors for bladder cancer, but no significant differences in other characteristics, including vitamin D levels. This pattern is consistent with decades of bladder cancer epidemiology. Smoking remains the single most important modifiable risk factor for the disease, and the significant difference in smoking status between the groups in this study underscores how strongly behavioral exposures dominate the risk landscape compared with the subtle contributions of individual genetic variants. The absence of a difference in vitamin D levels between patients and controls is itself noteworthy, given the ongoing debate about whether vitamin D status influences bladder cancer risk, and it suggests that in this cohort, circulating vitamin D did not distinguish cases from controls.

The negative finding also illustrates a broader and often underappreciated truth about genetic association studies: population context matters enormously. The same variant can appear protective in one population and neutral in another because of differences in allele frequencies, linkage with other nearby variants, environmental exposures, and the genetic background against which the variant operates. A 2025 systematic review in Discovery Oncology mapped the genetic landscape of CYP24A1 polymorphisms in cancer risk and highlighted this heterogeneity across studies. The Turkish results add an important data point for Caucasian populations, where these variants had never before been tested in relation to bladder cancer, and they caution against assuming that findings from Asian cohorts can be directly transplanted into European or Middle Eastern genetic contexts.

There are also technical reasons for restraint in interpreting any single-SNP result. Regulatory variants like rs1570669 and rs2762934 typically exert small effects on gene expression, and resources such as the GTEx project, which catalogs genetic regulatory effects across human tissues, and RegulomeDB, which annotates non-coding variants, provide only indirect evidence about how these particular SNPs might influence CYP24A1 activity in bladder tissue. The bladder does express both the vitamin D receptor and CYP24A1, and the local balance between vitamin D signaling and its degradation has been proposed as a mechanism relevant to vitamin D-based anticancer therapeutics. But translating that biochemical logic into a measurable difference in disease risk requires variants with substantial functional impact, large sample sizes, and careful control of confounding. With 152 cases and 178 controls, the present study was powered to detect only relatively strong genetic effects, and modest influences may simply have been invisible.

For now, the practical message is one of measured skepticism combined with scientific patience. The CYP24A1 rs2762934 and rs1570669 polymorphisms cannot be considered markers of bladder cancer susceptibility in the Turkish population based on this evidence, and no genetic test based on these variants should influence clinical practice. Yet the non-significant trend toward increased odds with the A alleles of both variants, the first Caucasian data on this question, and the continuing interest in vitamin D metabolism as a modifiable factor in cancer prevention all argue for follow-up work. Larger, multi-center cohorts that combine genotyping with detailed measurement of vitamin D status, smoking history, and tumor characteristics would be needed to determine whether these variants make any real contribution to bladder cancer risk, alone or in combination with other genes in the vitamin D pathway. Until then, the strongest advice for reducing bladder cancer risk remains unchanged: avoid tobacco, and pay attention to the environmental and occupational exposures that decades of research have firmly linked to this disease.

Subject of Research: Association of CYP24A1 gene polymorphisms with bladder cancer susceptibility in a Turkish population

Article Title: CYP24A1 rs1570669 and rs2762934 polymorphisms and bladder cancer susceptibility: a Turkish case-control study

Article References: Sulhan, H., Akkoç, Y., & Akgöllü, E. (2026). CYP24A1 rs1570669 and rs2762934 polymorphisms and bladder cancer susceptibility: a Turkish case-control study. Molecular Biology Reports, 53(1), Article 1700. https://doi.org/10.1007/s11033-026-12891-8

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12891-8

Keywords: bladder cancer, CYP24A1, single nucleotide polymorphisms, vitamin D metabolism, rs1570669, rs2762934, case-control study, genetic susceptibility, TaqMan genotyping, Turkish population, cancer epidemiology, 24-hydroxylase