Mendelian randomization study of spermine oxidase and cancer risk

Abstract

ABSTRACTImportanceSpermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of induced reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention.ObjectiveTo test the causality of SMOX levels with cancer risk using a Mendelian randomization analysis.Design, Setting, and ParticipantsWe performed a GWAS of spermidine/spermine ratio, from blood of 534 infants, to identify genetic variants associated with regulation of SMOX activity. In two additional data sets of 262 newborns and 508 adults, we quantified SMOX gene expression using RNA-sequencing and performed expression and methylation QTL lookups. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and various cancer types using GWAS summary statistics.Main Outcomes and MeasuresNeuroblastoma, gastric, lung, breast, prostate, and colorectal cancers.ResultsThe GWAS of spermidine/spermine ratio identified a genome-wide significant 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. rs1741315 was not associated with neuroblastoma (OR=0.95; 95% CI:0.88, 1.03; P=0.18), gastric (OR=0.99; 95% CI:0.95, 1.03; P=0.54), lung (OR=0.97; 95% CI:0.94, 1.00; P=0.08), breast (OR=0.99; 95% CI:0.96, 1.02; P=0.47), prostate (OR=0.98; 95% CI:0.96, 1.00; P=0.05) nor colorectal cancer (OR=1.03; 95% CI:0.99, 1.07; P=0.10). A PheWAS of rs1741315 did not reveal any associations with risk factors of the cancers tested.Conclusions and RelevanceGenetic 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. Further studies are needed to understand the effect of SMOX inhibition in relation to cancer risk.ARTICLE SUMMARYQuestionIs SMOX causally associated with risk of cancer?FindingsIn this Mendelian randomization study, genetically lower levels of SMOX were not associated with decreased risk of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer.MeaningThese findings do not support a causal association between SMOX activity and risk of cancer, suggesting that ongoing efforts to identify SMOX inhibitors for chemoprevention may not be successful.STRENGHTS AND LIMITATIONS-Previous studies which examined SMOX activity and cancer risk were susceptible to recall bias, confounding and reverse causation, none of which are concerns of this Mendelian randomization study.-Our genetic instrument explained a sizeable proportion of the variance of SMOX activity-We used summary statistics from the largest meta-analyses of primary cancer GWAS to date.-Elevated SMOX levels in cancer could also be due to environmental factors not captured by genetics.-Our genetic instrument was developed based on normal range SMOX activity data, thus additional genetic variants might play a role in aberrant expression of this enzyme.