Integrative Transcriptome-Wide Association Study With Expression Quantitative Trait Loci Colocalization Identifies a...

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Nasopharyngeal carcinoma (NPC) is prevalent in Asia, but its genetic basis is not fully understood.
• Identifying genetic factors is crucial for understanding NPC development and predisposition.

Purpose of the Study:

• To identify novel genetic susceptibility genes for nasopharyngeal carcinoma (NPC).
• To elucidate the functional mechanisms underlying NPC pathogenesis involving identified genes and pathways.

Main Methods:

• Performed a transcriptome-wide association study (TWAS) using NPC genetic data and epithelial tissue expression models.
• Conducted fine-mapping, eQTL colocalization, and genome-wide association studies (GWAS) to identify causal variants.
• Utilized functional assays to investigate the role of VAMP8 in NPC cell behavior and molecular mechanisms.

Main Results:

• Identified VAMP8 as a novel NPC susceptibility gene, with variant rs1058588 showing significant GWAS association.
• Demonstrated that VAMP8 promotes NPC cell proliferation, migration, and tumor growth.
• Uncovered a mechanism where rs1058588 affects VAMP8 expression via miR-185, and VAMP8 interacts with DHX9 to activate the NF-κB pathway.

Conclusions:

• VAMP8 is a key genetic contributor to nasopharyngeal carcinoma.
• The miR-185-VAMP8-DHX9-NF-κB axis plays a critical role in NPC pathogenesis.
• Findings provide insights into the genetic predisposition and molecular mechanisms of NPC.