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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.

Consumer purchase data (CPD) is a promising instrument to assess the impact of purchases on health, but is limited by the need for manual scanning, a lack of access to data from multiple retailers, and limited information on product data and health outcomes. Here we describe the My Purchases cohort, a web-app enabled, prospective collection of CPD, covering several large retail chains in Denmark, that enables linkage to health outcomes. The cohort included 459 participants as of July 03, 2023. Up to eight years of CPD have been collected, with 2,225,010 products purchased, comprising 223,440 unique products. We matched 88.5% of all products by product name or item number to one generic food database and three product databases. Combined, the databases enable analysis of key exposures such as nutrients, ingredients, or additives. We found that increasing the number of retailers that provide CPD for each consumer improved the stability of individual CPD profiles and when we compared kilojoule information from generic and specific product matches, we found a median modified relative difference of 0.23. Combined with extensive product databases and health outcomes, CPD could provide the basis for extensive investigations of how what we buy affects our health.

Background Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed. Methods We developed double batched sequencing where DNA samples are batch-sequenced twice — directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative ( n = 100) and a validation ( n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data. Results We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91–1.00 and 95% CI, 0.98–1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1 , TP53 , BRCA2 , APC , and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing. Conclusions Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.

Background: Neonatal herpes simplex virus (HSV) infection is life-threatening, with a mortality of up to 70–80% when disseminated, often due to vague symptoms and delayed treatment. Neonatal screening using dried blood spot (DBS) samples is among the most impactful preventative health measures ever implemented, but screening for HSV has not been investigated. Methods: We investigated high throughput multiplexed proteomics on DBS samples collected on days 2–3 of life from a nationwide cohort of neonates with HSV infection ( n  = 53) and matched controls. We measured 2941 proteins using the Olink Explore 3072 panels and proximity extension assays, followed by differential protein expression by Analysis of Variance with post-hoc correction and functional annotation. Results: Here, we show distinct protein profiles in neonates with disseminated HSV disease, with differences in 20 proteins compared to controls. These proteins are associated with innate and adaptive immune responses and cytokine activation. Conclusions: Our findings indicate the potential of neonatal screening for disseminated HSV disease to ensure early treatment and reduce the high mortality. Plain language summary Herpes simplex virus (HSV) infection in newborns has a 70% risk of death if infection becomes widespread in the body. Initial symptoms are often vague, leading to delayed treatment. Early dried blood spot (DBS) screening of newborns is very effective for identifying disorders present at birth, but its use to identify HSV infection has not been investigated. Here, we analysed DBS samples taken on days 2–3 of life from newborns developing HSV infection in the neonatal period. We identified 20 proteins that differed between those with widespread HSV infection compared to healthy babies. These findings suggest that HSV screening on DBS samples have the potential to detect severe infections early, enabling prompt treatment and reducing the risk of death. Dungu et al. use high throughput multiplexed proteomics on dried blood spot samples from neonates with herpes simplex virus infection. Distinct protein profiles were seen in proteins associated with innate and adaptive immune responses neonates with disseminated HSV disease compared to controls.

Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia. Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time. 15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis.

Antisense oligonucleotides that recruit RNase H and thereby cleave complementary messenger RNAs are being developed as therapeutics. Dose-dependent hepatic changes associated with hepatocyte necrosis and increases in serum alanine-aminotransferase levels have been observed after treatment with certain oligonucleotides. Although general mechanisms for drug-induced hepatic injury are known, the characteristics of oligonucleotides that determine their hepatotoxic potential are not well understood. Here, we present a comprehensive analysis of the hepatotoxic potential of locked nucleic acid-modified oligonucleotides in mice. We developed a random forests classifier, in which oligonucleotides are regarded as being composed of dinucleotide units, which distinguished between 206 oligonucleotides with high and low hepatotoxic potential with 80% accuracy as estimated by out-of-bag validation. In a validation set, 17 out of 23 oligonucleotides were correctly predicted (74% accuracy). In isolation, some dinucleotide units increase, and others decrease, the hepatotoxic potential of the oligonucleotides within which they are found. However, a complex interplay between all parts of an oligonucleotide can influence the hepatotoxic potential. Using the classifier, we demonstrate how an oligonucleotide with otherwise high hepatotoxic potential can be efficiently redesigned to abate hepatotoxic potential. These insights establish analysis of sequence and modification patterns as a powerful tool in the preclinical discovery process for oligonucleotide-based medicines.

Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia. Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time. 15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis.

Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia. Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time. 15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis.

-acetyltransferase 2 (NAT2) is the main enzyme metabolizing isoniazid and genotype-based treatment has been studied for years without becoming common practice. To investigate whether genotype-based isoniazid treatment is feasible in Greenland, we sequenced the coding sequence of and determined the NAT2 enzyme-activity by caffeine test. No additional genetic variants were identified in the coding sequence of , so that genotype status in 260 study participants could be assessed by a well-established 7-SNP panel. Studying the enzyme activity by the ratio of the two caffeine metabolites AFMU and 1X in 260 participants showed a high rate of slow phenotypes with intermediate or rapid genotype. These misclassifications were mainly observed in urine samples with pH<3, a deviation from the standard protocol due to the field work character of the study, where immediate pH adjustment to pH=3.5 was not possible. We excluded these samples. For the remaining 143 individuals with pH>3, we observed a moderate level of discrepancies (19 of the 116 individuals with intermediate or rapid genotype status having a slow phenotype). Further investigation showed that drinking coffee and not tea or cola was the most important factor for high levels of both metabolites. The concordance between phenotype and genotype status with regard to slow metabolism supported the recommendation of lower isoniazid doses in individuals with slow genotype status in order to avoid liver injury, a frequent side effect. The phenotypical variation observed for individuals with intermediate or rapid genotype status warrants further research before increased dosing of isoniazid can be recommended.

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from 9 contributing centers. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage (imputed to Haplotype Reference Consortium or 1000 Genomes phase 1 version 3 panels) accounting for population stratification. Fixed-effects meta-analysis was performed weighted by inverse standard error. Analysis included up to 19,003 individuals (7,530 affected) for primary teeth and 13,353 individuals (5,875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth (intronic within ALLC, Odds Ratio (OR) 0.85, Effect Allele Frequency (EAF) 0.60, p 4.13e-8) and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, p 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low (h2 of 1% [95% CI: 0%:7%] and 6% [95% CI 0%:13%] for primary and permanent dentitions, respectively) compared to corresponding within-study estimates (h2 of 28%, [95% CI: 9%:48%] and 17% [95% CI:2%:31%]) or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.