Vitamin D receptor rs2228570 (FokI) variant is associated with chronic tinnitus susceptibility

Tinnitus is a multifactorial condition with complex and not fully elucidated pathophysiology. Emerging evidence suggests that vitamin D deficiency and neuroinflammatory mechanisms may contribute to tinnitus development. Although vitamin D receptor (VDR) gene polymorphisms have been investigated in otologic disorders, their association with chronic tinnitus remains unclear. This study aimed to evaluate the relationship between VDR polymorphisms and chronic tinnitus susceptibility.

This case-control study included 208 participants (104 chronic tinnitus patients and 104 healthy controls). Four VDR polymorphisms (rs2228570/FokI, rs1544410/BsmI, rs7975232/ApaI, and rs731236/TaqI) were genotyped using real-time PCR. Genotype and allele frequencies were analyzed under dominant, recessive, and additive models. Haplotype distributions were estimated using the Expectation-Maximization algorithm. Bonferroni correction was applied for multiple testing. Cis-eQTL analyses were conducted using GTEx v8 data, and functional annotations were assessed using public databases.

Among the analyzed variants, only FokI showed a significant association with chronic tinnitus at the allelic level after multiple comparison correction (p = 0.011). The C allele was more frequent in patients, whereas the T allele appeared protective. No significant associations were observed for BsmI, ApaI, and TaqI. Haplotype analyses yielded nominal findings that did not remain significant after correction. Cis-eQTL evaluation revealed no significant relationship between FokI genotype and VDR expression levels in brain tissues or whole blood. Functional annotation suggested a potential effect on receptor isoform structure.

The VDR FokI polymorphism may be associated with susceptibility to chronic tinnitus. However, the underlying biological mechanisms remain to be elucidated and require further investigation.