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Fadista, João; Yakimov, Victor; Võsa, Urmo; Hansen, Christine S.; Kasela, Silva; Skotte, Line; Geller, Frank; Courraud, Julie; Esko, Tõnu; Kukuškina, Viktorija; Buil, Alfonso; Melbye, Mads; Werge, Thomas M.; Hougaard, David M.; Milani, Lili; Bybjerg-Grauholm, Jonas; Cohen, Arieh S.; Feenstra, Bjarke

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

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  • Media type: E-Article
  • Title: Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study
  • Contributor: Fadista, João; Yakimov, Victor; Võsa, Urmo; Hansen, Christine S.; Kasela, Silva; Skotte, Line; Geller, Frank; Courraud, Julie; Esko, Tõnu; Kukuškina, Viktorija; Buil, Alfonso; Melbye, Mads; Werge, Thomas M.; Hougaard, David M.; Milani, Lili; Bybjerg-Grauholm, Jonas; Cohen, Arieh S.; Feenstra, Bjarke
  • imprint: Springer Science and Business Media LLC, 2021
  • Published in: Scientific Reports
  • Language: English
  • DOI: 10.1038/s41598-021-97069-x
  • ISSN: 2045-2322
  • Keywords: Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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<jats:italic>SMOX</jats:italic>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<jats:italic>SMOX</jats:italic>locus (P = 1.34 × 10<jats:sup>–49</jats:sup>) explaining 32% of the variance. The lead SNP rs1741315 was also associated with<jats:italic>SMOX</jats:italic>gene expression in newborns (P = 8.48 × 10<jats:sup>–28</jats:sup>) and adults (P = 2.748 × 10<jats:sup>–8</jats:sup>) 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 &gt; 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the<jats:italic>SMOX</jats:italic>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.</jats:p>
  • Access State: Open Access