Functional and genetic divergence of aging-related TOMM40 polymorphisms in Alzheimer's disease: an integrative...

The etiology of late-onset Alzheimer's disease (AD) is only partly understood. Because TOMM40 is located within the APOE-TOMM40-APOC1 locus, its independent role remains unclear. This study aimed to assess the association of six TOMM40 polymorphisms with AD risk across five genetic models while integrating genome-wide, regulatory, and functional genomic evidence to clarify their potential biological roles.

A comprehensive literature search was conducted across five electronic databases. RevMan 5.1 was used for meta-analysis, including subgroup, meta-regression, and sensitivity analyses. To provide biological context, genome-wide data from IGAP/NIAGADS, AD-specific functional annotations from AGORA, and regulatory eQTL/sQTL evidence from GTEx were incorporated, with pathway enrichment using Enrichr.

Thirteen articles were included in the meta-analysis. rs2075650 showed a significantly increased AD risk across all genetic models, while rs157580 consistently demonstrated a protective effect. rs157581 was also associated with elevated risk, whereas rs8106922, rs11556505, and rs1160985 showed no significant associations. Bioinformatic analysis showed that rs2075650 and rs157581 reside within the APOE-linked LD block and affect TOMM40 splicing, whereas rs157580 demonstrated an LD-independent regulatory pattern, influencing the expression of genes involved in lipid- and amyloid-related pathways.

rs2075650, rs157580, and rs157581 show significant associations with AD risk. rs2075650 and rs157581 confer elevated risk, while rs157580 is protective. Integrated genomic evidence indicates that the risk variants act via TOMM40 splicing within the APOE locus, whereas the protective variant modulates expression of lipid- and amyloid-related genes, suggesting distinct mechanisms.