Journal Article

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

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

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114 / 631/208 / 631/208/1516 / 631/208/205 / 631/67 / Adult / Breast cancer / Cancer and Oncology / Cancer och onkologi / Clinical Medicine / Colorectal cancer / Colorectal carcinoma / Gene expression / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Neoplastic / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Health risks / Humanities and Social Sciences / Humans / Infant, Newborn / Klinisk medicin / Medical and Health Sciences / Medicin och hälsovetenskap / Mendelian Randomization Analysis - methods / multidisciplinary / Neonates / Neoplasms - etiology / Neoplasms - metabolism / Neoplasms - pathology / Neuroblastoma / Observational studies / Oxidation / Oxidoreductases Acting on CH-NH Group Donors - genetics / Phenotype / Polyamine Oxidase / Polymorphism, Single Nucleotide / Prostate / Prostate cancer / Quantitative Trait Loci / Reactive oxygen species / Science / Science (multidisciplinary) / Single-nucleotide polymorphism / Spermidine / Spermine / Statistical analysis