Multi-variant Genetic Panel for Genetic Risk of Opioid Addiction.

Over 116 million people worldwide have chronic pain and prescription dependence. In the US, opioids account for the majority of overdose deaths, and in 2014, almost 2 million Americans abused or were dependent on prescription opioids. Genetic factors may play a key role in opioid prescription addiction. Herein, we describe genetic variations between opioid addicted and non-addicted populations and derive a predictive model determining risk of opioid addiction. This case cohort study compares the frequency of 16 single nucleotide polymorphisms involved in the brain reward pathways in patients with and without opioid addiction. Data from 37 patients with prescription opioid or heroin addiction and 30 age and gender matched controls were used to design the predictive score. The predictive score was then tested on an additional 138 samples to determine generalizabilty. Results for Method Derivation of Observed data: ROC statistic=0.92, sensitivity=82% (95% CI: 66-90), specificity=75% (95% CI:56-87). TreeNet "learn" data: ROC statistic=0.92, sensitivity=92%, specificity=90%, precision=92%, and overall correct=91%. Results of Generalizability data: Sensitivity=97% (95% CI: 90 to 100), specificity=87% (95% CI: 86 to 93), positive likelihood ratio=7.3 (95% CI: 4.0 to 13.5), and negative likelihood ratio=0.03 (95% CI: 0.01 to 0.13). This negative likelihood ratio can be used as an evidence based measure to exclude patients with a high risk of opioid addicition or substance use disorder. By identifying patients with a lower risk for opioid addiction, our model may inform therapeutic decisions.

Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration.

Age-related macular degeneration (AMD) is characterized by complex interactions between genetic and environmental factors. Here we genotyped the selected 25 single-nucleotide polymorphisms (SNPs) in 983 cases with advanced AMD and 271 cases with intermediate AMD and build an AMD life-risk score model for assessment of progression from intermediate to advanced AMD. We analyzed the performance of the prediction model for geographic atrophy progressors or choroidal neovascularization progressors versus non-progressors based on the 25 SNPs plus body mass index and smoking status. Our results suggest that a class prediction algorithm can be used for the risk assessment of progression from intermediate to late AMD stages. The algorithm could also be potentially applied for therapeutic response, and toward personalized care and precision medicine.

The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2).

BACKGROUND: Regulation of production of the translational apparatus via the stringent factor ppGpp in response to amino acid starvation is conserved in many bacteria. However, in addition to this core function, it is clear that ppGpp also exhibits genus-specific regulatory effects. In this study we used Affymetrix GeneChips to more fully characterize the regulatory influence of ppGpp synthesis on the biology of Streptomyces coelicolor A3(2), with emphasis on the control of antibiotic biosynthesis and morphological differentiation. RESULTS: Induction of ppGpp synthesis repressed transcription of the major sigma factor hrdB, genes with functions associated with active growth, and six of the thirteen conservons present in the S. coelicolor genome. Genes induced following ppGpp synthesis included the alternative sigma factor SCO4005, many for production of the antibiotics CDA and actinorhodin, the regulatory genes SCO4198 and SCO4336, and two alternative ribosomal proteins. Induction of the CDA and actinorhodin clusters was accompanied by an increase in transcription of the pathway regulators cdaR and actII-ORF4, respectively. Comparison of transcriptome profiles of a relA null strain, M570, incapable of ppGpp synthesis with its parent M600 suggested the occurrence of metabolic stress in the mutant. The failure of M570 to sporulate was associated with a stalling between production of the surfactant peptide SapB, and of the hydrophobins: it overproduced SapB but failed to express the chaplin and rodlin genes. CONCLUSION: In S. coelicolor, ppGpp synthesis influences the expression of several genomic elements that are particularly characteristic of streptomycete biology, notably antibiotic gene clusters, conservons, and morphogenetic proteins.