Genetic insights into vitamin D receptor polymorphisms and spinal tuberculosis risk: Discovery of novel SNP variant

Limited findings on the role of genetic susceptibility in spine tuberculosis (STB) including Vitamin D receptor (VDR) gene polymorphism emphasize the need to explore it further especially with clinical severity in areas of huge disease burden. Current study aimed to investigate the genotype and allele frequency of VDR-Fok-1 & Apa-1 in local population of Pakistan, and their association with clinical severity and histological features . Forty-three adult STB patients undergoing spine surgery and 43 age & sex matched healthy controls were recruited after informed consent. Demographic and clinical profile, X-rays, T1-T2W MRI & post-surgical tissues were obtained from patients for analyses. Sanger sequencing was done to analyze Fok-1 and Apa-1 polymorphisms on the blood samples of patients and controls. A novel SNP; rs11574113 was also identified while investigating the sequencing data of Apa-1. There was significant association between STB and heterozygous (Ff), homozygous (ff) genotype of Fok-1 ( p = 0.003) and heterozygous (Rr) genotype of rs11574113 ( p = 0.02). Wild-type (FF) Fok-1, homozygous (aa) Apa-1 and heterozygous (Rr) genotype of rs11574113 polymorphisms were associated with increased vertebral involvement ( p = 0.01), complete vertebral bodies ( p = 0.001), intervertebral-disc collapse ( p = 0.002) and higher Pfirrmann grades ( p = 0.03). Apa-1 polymorphism was also found to be associated with well-formed granuloma ( p = 0.01) on histology. RegulomeDB and LDlink analyses revealed a novel rs11574113–rs7975232 haplotype (R 2 = 1.0) with regulatory roles, distinct from rs2228570's independent effects. The study suggests significant associations of VDR gene polymorphisms Fok-1 and rs11574113 with risk and severity of STB in the Pakistani population, highlighting rs11574113 as a novel SNP not previously reported. • Significant associations were found between VDR gene polymorphisms and severity of spinal tuberculosis in the Pakistani population. • A novel SNP was identified linked to increased vertebral damage, disc collapse, and higher Pfirrmann grades signifying potential role in TB spine. • Identification of new regulatory haplotypes highlights need to consider genetic variants in TB-endemic regions for better risk stratification