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

Fadista, João LU ; Yakimov, Victor ; Võsa, Urmo ; Hansen, Christine S. ; Kasela, Silva ; Skotte, Line ; Geller, Frank ; Courraud, Julie ; Esko, Tõnu and Kukuškina, Viktorija , et al. (2021) In Scientific Reports 11(1).
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... (More)

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 × 10–49) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10–28) and adults (P = 2.748 × 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.

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organization
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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
issue
1
article number
17463
publisher
Nature Publishing Group
external identifiers
  • scopus:85113945237
  • pmid:34465810
ISSN
2045-2322
DOI
10.1038/s41598-021-97069-x
language
English
LU publication?
yes
id
26bf45a1-7b43-4015-9831-085fd805529e
date added to LUP
2021-09-17 09:00:38
date last changed
2022-09-10 05:41:42
@article{26bf45a1-7b43-4015-9831-085fd805529e,
  abstract     = {{<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 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 × 10<sup>–49</sup>) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10<sup>–28</sup>) and adults (P = 2.748 × 10<sup>–8</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 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.</p>}},
  author       = {{Fadista, João and Yakimov, Victor and Võsa, Urmo and Hansen, Christine S. and Kasela, Silva and Skotte, Line and Geller, Frank and Courraud, Julie and Esko, Tõnu and Kukuškina, Viktorija and Buil, Alfonso and Melbye, Mads and Werge, Thomas M. and Hougaard, David M. and Milani, Lili and Bybjerg-Grauholm, Jonas and Cohen, Arieh S. and Feenstra, Bjarke}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Genetic regulation of spermine oxidase activity and cancer risk : a Mendelian randomization study}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-97069-x}},
  doi          = {{10.1038/s41598-021-97069-x}},
  volume       = {{11}},
  year         = {{2021}},
}