Expressional profiling of prostate cancer risk SNPs at 11q13.5 identifies DGAT2 as a new target gene.
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.
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Riikka
0000-0001-8142-5462
R
Nurminen
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Tommi
T
Rantapero
Department of Biosciences, University of Helsinki, Helsinki, Finland.
Swee C
SC
Wong
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Daniel
D
Fischer
Institute of Biomedicine & Genome-Scale Biology Research Program, Faculty of Medicine, Biomedicum, University of Helsinki, Helsinki, Finland.
Rainer
R
Lehtonen
Department of Urology and Prostate Cancer Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.
Teuvo L J
TL
Tammela
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.
Matti
M
Nykter
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Tapio
T
Visakorpi
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Tiina
T
Wahlfors
BioMediTech and Prostate Cancer Research Center, University of Tampere, Tampere, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
Johanna
J
Schleutker
D000368:Aged; D000369:Aged, 80 and over; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D040641:Quantitative Trait Loci / Q000235:genetics
C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase