Genetics of alcoholic and nonalcoholic fatty liver disease

Excess alcohol consumption with consequent alcoholic liver disease (ALD) and metabolic syndrome-related nonalcoholic fatty liver disease (NAFLD) are recognized as the most common causes of liver dysfunction worldwide. However, although the majority of heavy drinkers and individuals with obesity/insulin resistance will develop steatosis, only a minority progress to steatohepatitis, fibrosis, and cirrhosis. Both ALD and NAFLD are best considered complex disease traits where subtle interpatient genetic variations and environment interact to produce disease phenotype and determine disease progression. A decade after the sequencing of the human genome, the development of technologies to support the comprehensive study of genomic variation has begun to provide new insights into the modifier genes that contribute to this interpatient variation. Here we review the current status of the field with particular focus on advances from recent genome-wide association studies and their translation into a better mechanistic understanding of pathogenesis.     

Viral determinants of HIV-1 macrophage tropism

Macrophages are important target cells for HIV-1 infection that play significant roles in the maintenance of viral reservoirs and other aspects of pathogenesis. Understanding the determinants of HIV-1 tropism for macrophages will inform HIV-1 control and eradication strategies. Tropism for macrophages is both qualitative (infection or not) and quantitative (replication capacity). For example many R5 HIV-1 isolates cannot infect macrophages, but for those that can the macrophage replication capacity can vary by up to 1000-fold. Some X4 viruses are also capable of replication in macrophages, indicating that cellular tropism is partially independent of co-receptor preference. Preliminary data obtained with a small number of transmitted/founder viruses indicate inefficient macrophage infection, whereas isolates from later in disease are more frequently tropic for macrophages. Thus tropism may evolve over time, and more macrophage tropic viruses may be implicated in the pathogenesis of advanced HIV-1 infection. Compartmentalization of macrophage-tropic brain-derived envelope glycoproteins (Envs), and non-macrophage tropic non-neural tissue-derived Envs points to adaptation of HIV-1 quasi-species in distinct tissue microenvironments. Mutations within and adjacent to the Env-CD4 binding site have been identified that determine macrophage tropism at the entry level, but post-entry molecular determinants of macrophage replication capacity involving HIV-1 accessory proteins need further definition.     

Recurrent costs of HIV/AIDS-related health services in Rwanda: implications for financing

Objective To estimate recurrent costs per patient and costs for a national HIV/AIDS treatment programme model in Rwanda. Methods A national HIV/AIDS treatment programme model was developed. Unit costs were estimated so as to reflect necessary service consumption of people living with HIV/AIDS (PLWHA). Two scenarios were calculated: (1) for patients/clients in the year 2006 and (2) for potential increases of patients/clients. A sensitivity analysis was conducted to test the robustness of results. Results Average yearly treatment costs were estimated to amount to 504 US$ per patient on antiretroviral therapy (ART) and to 91 US$ for non‐ART patients. Costs for the Rwandan HIV/AIDS treatment programme were estimated to lie between 20.9 and 27.1 million US$ depending on the scenario. ART required 9.6 to 11.1 million US$ or 41–46% of national programme costs. Treatment for opportunistic infections and other pathologies consumed 7.1 to 9.3 million US$ or 34% of total costs. Conclusion Health Care in general and ART more specifically is unaffordable for the vast majority of Rwandan PLWHA. Adequate resources need to be provided not only for ART but also to assure treatment of opportunistic infections and other pathologies. While risk‐pooling may play a limited role in the national response to HIV/AIDS, considering the general level of poverty of the Rwandan population, no appreciable alternative to continued donor funding exists for the foreseeable future.     

A lipid to treat non-alcoholic fatty liver disease - the dawn of 'lipo-rehabilitation'?

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl sidechains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatictriglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.     

Erythroid cell adhesion molecules Lutheran and LW in health and disease

The Lutheran and LW glycoproteins are blood group-active proteins found at the surface of human red cells. The Lutheran glycoprotein (Lu gp) is a member of the immunoglobulin superfamily (IgSF) that binds the extracellular matrix protein laminin, in particular, laminin isoforms containing the alpha 5 subunit. The LW glycoprotein (LW gp), also an IgSF member, has substantial sequence homology with the family of intercellular adhesion molecules (ICAMs). LW gp binds the integrin very late antigen-4 (VLA-4, alpha 4 beta 1) and alpha V-containing integrins. Studies on the expression of LW and Lu gps during erythropoiesis utilizing in vitro cultures of haemopoietic progenitor cells have shown that LW gp expression precedes that of Lu gp. These observations have led to the suggestion that LW gp on erythroblasts may interact with VLA-4 on macrophages to stabilize erythroblastic islands in normal bone marrow and that Lu gp may facilitate trafficking of more mature erythroid cells to the sinusoidal endothelium where alpha 5-containing laminins are known to be expressed. Levels of Lu gp and LW gp expression on sickle red cells are greater than on normal red cells and sickle red cells adhere to alpha 5-containing laminins. These data suggest that the Lu and LW molecules may contribute to the vaso-occlusive events associated with episodes of acute pain in sickle cell disease.     

Estimation of the Number of Binding Sites for a Murine Monoclonal Anti-Lub on Human Erythrocytes

The number of Lub antigen sites on the human erythrocyte membrane, as recognised by the murine monoclonal antibody BRIC-108, has been determined. The number of antibody molecules bound per cell on one example of cells of the phenotype Lu(a-b-) with recessive inheritance was an average of around 200 in replicate determinations, which probably represents non-specific antibody binding. A similar number of antibody molecules to this bound to trypsin- or pronase-treated normal cells or cells of the Lu(a-b-) phenotype associated with the inheritance of the X-borne gene, XS2. The number of binding sites on three examples of cells of the phenotype Lu(a-b-) with dominant inheritance was from 440 to 690. A variation in the number of binding sites per cell from 1,640 to 4,070 was found in five individuals with the phenotype Lu(a-b+) and from 850 to 1,820 in four individuals with the phenotype Lu(a+b+). Four individuals with the Lu(a+b-) phenotype had an average of 480 binding sites per cell. The Lub antigen therefore appears to a have low-site density and a variable level of expression on the erythrocyte surface.     

Bioresorbable vascular scaffold to treat in‐stent restenosis: Single‐center experience

Aims

The management of patients with in‐stent restenosis (ISR) is still a major clinical challenge even in the era of drug‐eluting stents (DES). Recent studies have demonstrated acceptable clinical outcomes for the everolimus‐eluting bioresorbable vascular scaffold (BVS) ABSORB? in patients with stable coronary artery disease but data are scarce on its use in patients with ISR. We report the long‐term results of our preliminary experience with this novel approach at our institution.

Methods and Results

We investigated the safety and efficacy of BVS implantation to treat ISR. 34 consecutive patients (37 lesions) underwent PCI for ISR with BVS implantation between May 2013 and June 2015 at our institution and were included in the current analysis. Follow‐up was available in 91.9% of the patients. Mean follow‐up period was 801.9 ± 179 days. One patient had definite scaffold thrombosis (ScT) 2 months after stent implantation which was treated with DES. Five patients (six lesions) experienced target lesion revascularization (TLR). The composite endpoint rate of TLR, ScT, myocardial infarction, and death occured in 6/37 lesions at follow‐up (16.2%).

Conclusions

These real‐world data using BVS in patients with ISR demonstrates that ISR treatment with ABSORB? BVS is feasible but could have slightly higher target lesion failure rates as compared to DES. This proof of concept could be hypothesis‐generating for larger randomized controlled studies.

     

Decanalization of wing development accompanied the evolution of large wings in high-altitude Drosophila

In higher organisms, the phenotypic impacts of potentially harmful or beneficial mutations are often modulated by complex developmental networks. Stabilizing selection may favor the evolution of developmental canalization—that is, robustness despite perturbation—to insulate development against environmental and genetic variability. In contrast, directional selection acts to alter the developmental process, possibly undermining the molecular mechanisms that buffer a trait’s development, but this scenario has not been shown in nature. Here, we examined the developmental consequences of size increase in highland Ethiopian Drosophila melanogaster. Ethiopian inbred strains exhibited much higher frequencies of wing abnormalities than lowland populations, consistent with an elevated susceptibility to the genetic perturbation of inbreeding. We then used mutagenesis to test whether Ethiopian wing development is, indeed, decanalized. Ethiopian strains were far more susceptible to this genetic disruption of development, yielding 26 times more novel wing abnormalities than lowland strains in F2 males. Wing size and developmental perturbability cosegregated in the offspring of between-population crosses, suggesting that genes conferring size differences had undermined developmental buffering mechanisms. Our findings represent the first observation, to our knowledge, of morphological evolution associated with decanalization in the same tissue, underscoring the sensitivity of development to adaptive change.Canalization describes the property of some biological traits to remain constant in the face of environmental and genetic changes (1–6). This phenomenon has important implications for the relationship between genetic and phenotypic variation. By masking the phenotypic effects of genetic changes, canalization may inhibit phenotypic evolution while allowing hidden genetic variation to accumulate. If canalization is overcome by environmental and/or genetic changes, this reservoir of functional variation may then be exposed. For example, Waddington (7) selected Drosophila for a missing cross-vein trait that initially only appeared in a stressful high-temperature environment but after selection, manifested under normal conditions as well. A molecular case study of canalization was provided by Rutherford and Lindquist (8), who found that Drosophila with a disabled chaperone protein (the heat shock protein Hsp90) showed a suite of developmental abnormalities. These abnormalities varied based on genetic background and environment and could be selected for Hsp90 independence. Other studies have also found that selection in the laboratory can alter developmental stability (9–12), and Hayden et al. (13) found that in vitro directional selection on ribozyme activity led to reduced genetic and environmental robustness.Canalization is difficult to disentangle from selective constraint, which complicates its study in natural populations. A rare potential example comes from the blowfly Lucilia cuprina, in which the evolution of insecticide resistance was accompanied by prolonged development and bristle asymmetry (14). Those disadvantages were subsequently reversed by the evolution of an unlinked modifier locus (15). Here, the initial cost of adaptation may have been because of pleiotropic decanalizing effects of the insecticide resistance mutation itself. Or given the contrast between the adaptive and decanalized phenotypes, a linked deleterious variant might have been fixed along with the resistance allele and later compensated by the modifier gene.Canalization might evolve because of stabilizing selection favoring the same phenotypic optimum in the face of environmental and genetic variability [as shown in the case of environmental robustness (16)], or canalization might arise from inherent properties of the biological system (17). Particularly in the former scenario, it seems possible that directional selection might undermine canalization: if selection for a new phenotypic optimum alters the developmental process, then the molecular mechanisms that had previously buffered the ancestral phenotype might fail to buffer the novel phenotype. Hence, it seems possible that recently evolved traits may show reduced canalization (until new or modified buffering mechanisms can evolve), but no such example has been reported from nature.Here, we describe a natural instance of decanalization associated with a recently evolved morphological structure, focusing on wing size and developmental stability in a high-altitude (>3,000 m) Ethiopian population of Drosophila melanogaster. Although globally distributed today, this human-commensal species probably originated in the lowlands of southern central Africa (18). The species’ arrival in Ethiopia may have roughly coincided with its crossing of the Sahara [∼10,000 y ago (19, 20)]. Highland Ethiopian flies are morphologically divergent from other D. melanogaster populations, featuring striking melanism (21), larger body size, and larger wings (Fig. 1) with distinct shape (22).Open in a separate windowFig. 1.Morphological comparisons of D. melanogaster from the Ethiopian highlands and an ancestral range Zambia population. Ethiopian strains have (A vs. B) larger body size and (C vs. D) wing size. (E) The distribution of wing widths among outbred individuals shows almost no overlap between populations. Detailed size data are given in Dataset S1.Past studies have shown that the Drosophila wing provides a convenient visible readout of development, allowing, for example, the study of variation unmasked by specific mutations (23, 24). This study repurposes mutagenesis as a generalized genetic perturbation to assess whether wing size evolution in Ethiopian D. melanogaster has undermined the stability of wing development. Initially, our observation of frequent wing abnormalities in Ethiopian inbred strains motivated the hypothesis of decanalized wing development. Mutagenesis experiments confirmed that de novo mutations were far more likely to produce wing defects in the Ethiopian strains than in the smaller-winged Zambia population (whereas a control trait showed no such difference), implying less buffered development of Ethiopian wings. A final mutagenesis experiment confirmed that wing size and decanalization were inherited together in the advanced generation offspring of an Ethiopia–Zambia cross, implying that alleles conferring larger Ethiopian wings contributed to destabilized development.