Genetic determinants of drug-induced gingival overgrowth

Drug-induced gingival overgrowth (DIGO) is a multifactorial adverse effect associated with calcium channel blockers and antiepileptic drugs, yet genetic susceptibility-particularly in Asian populations-remains poorly defined. We performed whole-genome sequencing in 74 Thai individuals, including 36 DIGO cases and 38 drug-exposed nonresponder controls. A genome-wide association study was conducted with adjustment for amlodipine exposure, which showed a significant association with DIGO. Complementary analyses included gene-based testing using Multi-marker Analysis of GenoMic Annotation, fine-mapping with Sum of Single Effects, haplotype analysis, and receiver operating characteristic-based risk modeling. Although no single nucleotide polymorphisms (SNPs) reached genome-wide significance, we identified 350 lead SNPs across 34 genes showing strong associations with DIGO (p < 0.001). After multiple-testing correction, six genes/SNPs remained statistically significant (p < 0.05), representing the most robust findings. Haplotype analysis implicated TTC7B, RWDD1, TOM1L1, C1QL2, and BBS1 as DIGO risk genes. These genes, not previously linked to DIGO, are involved in cellular trafficking, phosphoinositide signaling, ciliary function, and protein regulation. Our findings indicate that DIGO susceptibility is driven by genetically determined cellular response pathways in the presence of amlodipine rather than by pharmacokinetic mechanisms. The absence of associations with CYP2C9 and HLA variants previously reported in other populations highlights the importance of ethnically diverse pharmacogenomic studies.