Susceptibility to pseudoexfoliation linked to intronic variant rs4926246 in CACNA1A: Evidence from an Indian population study.

Pseudoexfoliation (PEX) is an age-related, complex systemic disorder of protein aggregopathy. It is characterized by the extracellular fibril depositions, termed PEX fibrils, initially observed in various organ tissues during pseudoexfoliation syndrome (PEXS) and with significant prominence in the eye during advanced pseudoexfoliation glaucoma (PEXG). The study explores the association between CACNA1A (calcium channel, voltage-dependent, P/Q type, alpha 1 A subunit) variants and PEX in an Indian population. The investigation involved genotyping one intronic single nucleotide polymorphism (SNP), rs4926244, and three tag SNPs using the Sanger and TaqMan genotyping approaches in a cohort of 300 controls and 300 PEX patients (including 200 PEXS and 100 PEXG cases). Findings from the present study revealed a significant association at both allelic and genotypic levels for rs4926246, whereas rs4926244 showed association only at the genotypic level with PEX. Functional assays demonstrated increased mRNA expression linked to the risk genotype of both variants and luciferase reporter assays indicated an allele-specific regulatory effect of rs4926246.While in silico analysis predicted potential transcription factor binding sites for c-Myc and Hypoxia-inducing factor-1 (HIF-1) at the rs4926246 locus, electrophoretic mobility shift assay (EMSA) validated that only the "T" variant showed the reduced binding affinity with c-Myc compared to the protective variant "C". Our study identifies rs4926246, an intronic variant strongly associated with both PEXS and PEXG, potentially influencing gene expression and protein binding, warranting further investigation into its role in PEX pathogenesis.