Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics

<p>Abstract</p> <p>Background</p> <p>One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology.</p> <p>Methods</p> <p>We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (<it>CFH</it>) on chromosome 1q25 and variants in the <it>ARMS2</it>/HtrA serine peptidase 1 (<it>HTRA1</it>) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data.</p> <p>Results</p> <p>In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of <it>ARMS2</it>/<it>HTRA1 </it>rs1049331.</p> <p>Conclusions</p> <p>These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified.</p

Catabolic Pathways and Enzymes Involved in Anaerobic Methane Oxidation

Microbes use two distinct catabolic pathways for life with the fuel methane: aerobic methane oxidation carried out by bacteria and anaerobic methane oxidation carried out by archaea. The archaea capable of anaerobic oxidation of methane, anaerobic methanotrophs (ANME), are phylogenetically related to methanogens. While the carbon metabolism in ANME follows the pathway of reverse methanogenesis, the mode of electron transfer from methane oxidation to the terminal oxidant is remarkably versatile. This chapter discusses the catabolic pathways of methane oxidation coupled to the reduction of nitrate, sulfate, and metal oxides. Methane oxidation with sulfate and metal oxides are hypothesized to involve direct interspecies electron transfer and extracellular electron transfer. Cultivation of ANME, their mechanisms of energy conservation, and details about the electron transfer pathways to the ultimate oxidants are rather new and quickly developing research fields, which may reveal novel metabolisms and redox reactions. The second section focuses on the carbon catabolism from methane to CO2 and the biochemistry in ANME with its unique enzymes containing Fe, Ni, Co, Mo, and W that are compared with their homologues found in methanogens

Anaerobic Methane Oxidizers

The anaerobic oxidation of methane (AOM) with sulfate as the final electron acceptor according to (CH4 + SO4 2− → HCO3 − + HS− + H2O) is the major sink of methane in the oceans and hence a significant process in the global carbon cycle and methane budget. Anaerobic methane oxidizing archaea (ANME) and sulfate-reducing bacteria (SRB) are assumed to act as a syntrophic consortium where the archaeal partner activates and metabolizes methane, leading to an intermediate that is scavenged as electron donor by the sulfate-reducing partner. All known anaerobic methanotrophs are related to the methanogenic Euryarchaeota. Recently, much has been learned about the distribution, activity, and physiology of the ANME, however, not a single member of these groups has been obtained in culture and the biochemical functioning of AOM remains unknown

Anaerobic Methane Oxidizers

The anaerobic oxidation of methane (AOM) with sulfate as the final electron acceptor according to the net reaction CH4 + SO42- -> HCO3- -> HS- + H2O is the major sink of methane in the ocean floor and hence a significant process in the marine methane budget and the global carbon cycle. Since its discovery, much has been learned about the distribution of the AOM process, its activity in different settings, and connections to other metabolic reactions in the seafloor. AOM is performed by consortia of anaerobic methane-oxidizing archaea (ANME) and sulfate-reducing bacteria (SRB). Since all known ANME and most of their partner bacteria have so far resisted isolation, the physiology of both organisms has been largely inferred from culture-independent approaches on natural enrichments or enrichment cultures. All known ANME are related to methanogenic Euryarchaeota, and as such they reverse the methanogenesis pathway to activate and completely oxidize methane. The reducing equivalents are shuttled to the partner bacteria, which use them for sulfate reduction. Recently, evidence has been found for ANME that can use nitrate or iron as electron acceptors. The exact mechanisms for the required exchange of reducing equivalents in AOM and their genetic codes are yet poorly understood, but recently discovered accumulations of cytochromes and nanowire connections in the intercellular space of the consortia suggest direct electron transfer between both partners