Expressional Profiling of Prostate Cancer Risk SNPs at 11q13.5 Identifies DGAT2 as a New Target Gene

Genes Chromosomes Cancer. 2016 Aug;55(8):661-73. doi: 10.1002/gcc.22368. Epub 2016 May 24.

Abstract

A total of nine non-coding variants on 11q13.5 predispose men to prostate cancer (PrCa). rs200331695 within the EMSY intron is associated with aggressive PrCa and two high linkage disequilibrium (LD) groups of single-nucleotide polymorphisms (SNPs) in the intergenic region are associated with PrCa death. Here, the cis-effect of the SNPs on gene expression using expression quantitative trait loci analysis was investigated. The regulatory potential was screened in prostate tumors (n = 41) and in whole blood (n = 99). The results were validated in a second tumor set (n = 41), in lymphoblastoid cell lines (LCLs) (n = 38), and using the GTEx Portal. The effects of haplotypes were analyzed in the whole blood. The high LD SNPs (rs143975731, rs12277366, rs2155225, and rs2155222) were associated with DGAT2 expression in both tumors sets (screening P = 0.035-0.043; validation P = 0.005-0.018). The PrCa death-associated alleles decreased the expression by two-fold. rs200331695 decreased DGAT2 expression in LCLs (P = 0.006). The findings of SNPs regulating CAPN5 (P = 0.026-0.046) and AP001189.4 (P = 0.03-0.039) in the whole blood were not observed in LCLs, but the association with AP001189.4 expression was validated via the GTEx Portal (P = 8.7 × 10(-5) to 4.3 × 10(-4) ), which suggests that the high LD intergenic SNPs exert a tissue-dependent effect on the expression of two genes. No haplotypes including the risk SNPs at 11q13.5 were associated with gene expression and PrCa. The findings indicate the functionality of the PrCa death-predisposing SNPs rs143975731, rs12277366, rs2155225, and rs2155222 as DGAT2 regulators in prostate tumors. © 2016 Wiley Periodicals, Inc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Chromosomes, Human, Pair 11 / genetics
  • Diacylglycerol O-Acyltransferase / biosynthesis
  • Diacylglycerol O-Acyltransferase / genetics*
  • Gene Expression Regulation, Neoplastic
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Haplotypes / genetics
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Quantitative Trait Loci / genetics

Substances

  • DGAT2 protein, human
  • Diacylglycerol O-Acyltransferase