Variants at IRX4 as prostate cancer expression quantitative trait loci

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Genome-wide association studies (GWAS) have identified numerous genetic loci associated with prostate cancer risk.
• Some risk variants may function as regulatory elements, influencing gene expression, known as cis-expression quantitative trait loci (cis-eQTLs).
• Tissue specificity of cis-eQTLs is crucial for understanding their functional impact.

Purpose of the Study:

• To determine if GWAS-identified prostate cancer risk loci function as cis-eQTLs in human prostate tumor tissues.
• To investigate the tissue-specific regulatory effects of prostate cancer risk variants.
• To identify potential prostate cancer risk genes influenced by these variants.

Main Methods:

• Genotyping of 59 prostate cancer risk-associated single-nucleotide polymorphisms (SNPs) in 50 prostate cancer samples.
• Performing cis-eQTL analysis of transcripts within two megabase windows of identified SNPs in paired primary tumors.
• Comparative cis-eQTL analysis in lymphoblastoid cell lines.

Main Results:

• Twenty-seven significant transcript-genotype associations (false discovery rate ≤10%) were identified in prostate tumor tissues.
• No significant associations were found when performing equivalent cis-eQTL analysis in lymphoblastoid cell lines.
• The top cis-eQTL involved the IRX4 transcript and SNP rs12653946, with evidence of population specificity.

Conclusions:

• Cis-eQTL analysis in relevant human tissues, even with small sample sizes, is effective for prioritizing functional follow-up of GWAS findings.
• The IRX4 gene, regulated by a prostate cancer risk variant, is validated as a potential prostate cancer risk gene.
• Tissue-specific regulatory effects of GWAS loci are critical for understanding prostate cancer etiology.