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 × 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.
Highlights
Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine
SMOX has been reported as a source of induced reactive oxygen species (ROS) associated with neuroblastoma, gastric, lung, breast, prostate and colon cancers[14,15,16,17,18,19,20], implying that inhibition of SMOX could be a target for chemoprevention[3]
The Genome-wide association studies (GWAS) of spermidine/spermine ratio reflecting SMOX activity, was based on dried blood spot samples taken during routine newborn screening from 534 individuals of Danish ancestry, recruited in a matched case–control study of infantile hypertrophic pyloric stenosis (IHPS), as previously described[22,23] (SSI-IHPS cohort)
Summary
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. We 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. 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. SMOX has been reported as a source of induced reactive oxygen species (ROS) associated with neuroblastoma, gastric, lung, breast, prostate and colon cancers[14,15,16,17,18,19,20], implying that inhibition of SMOX could be a target for chemoprevention[3]. A GWAS could potentially detect genetic determinants of SMOX activity that might serve as instruments to assess the causality of SMOX on cancer using a Mendelian randomization framework[21]
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