Genetic regulation of spermine oxidase activity and cancer risk : a Mendelian randomization study

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Fadista , J , Yakimov , V , Vosa , U , Hansen , C S , Kasela , S , Skotte , L , Geller , F , Courraud , J , Esko , T , Kukuskina , V , Buil , A , Melbye , M , Werge , T M , Hougaard , D M , Milani , L , Bybjerg-Grauholm , J , Cohen , A S & Feenstra , B 2021 , ' Genetic regulation of spermine oxidase activity and cancer risk : a Mendelian randomization study ' , Scientific Reports , vol. 11 , no. 1 , 17463 . https://doi.org/10.1038/s41598-021-97069-x

Title: Genetic regulation of spermine oxidase activity and cancer risk : a Mendelian randomization study
Author: Fadista, Joao; Yakimov, Victor; Vosa, Urmo; Hansen, Christine S.; Kasela, Silva; Skotte, Line; Geller, Frank; Courraud, Julie; Esko, Tonu; Kukuskina, Viktorija; Buil, Alfonso; Melbye, Mads; Werge, Thomas M.; Hougaard, David M.; Milani, Lili; Bybjerg-Grauholm, Jonas; Cohen, Arieh S.; Feenstra, Bjarke
Contributor organization: Institute for Molecular Medicine Finland
Date: 2021-08-31
Language: eng
Number of pages: 9
Belongs to series: Scientific Reports
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-021-97069-x
URI: http://hdl.handle.net/10138/335415
Abstract: Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 x 10(-49)) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 x 10(-28)) and adults (P = 2.748 x 10(-8)) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention.
Subject: ORNITHINE-DECARBOXYLASE ACTIVITY
POLYAMINE METABOLISM
ASSOCIATION ANALYSIS
SUSCEPTIBILITY LOCI
ADENOMA RECURRENCE
VARIANTS
GENOTYPE
3111 Biomedicine
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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