Genetic loci associated with plasma phospholipid N-3 fatty acids: A Meta-Analysis of Genome-Wide association studies from the charge consortium

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10-64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10-58) and docosapentaenoic acid (DPA, p = 4×10-154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10-12) and DPA (p = 1×10-43) and lower docosahexaenoic acid (DHA, p = 1×10-15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10-8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries

Persistent Expression of Hepatitis C Virus Non-Structural Proteins Leads to Increased Autophagy and Mitochondrial Injury in Human Hepatoma Cells

HCV infection is a major cause of chronic liver disease and liver cancer in the United States. To address the pathogenesis caused by HCV infection, recent studies have focused on the direct cytopathic effects of individual HCV proteins, with the objective of identifying their specific roles in the overall pathogenesis. However, this approach precludes examination of the possible interactions between different HCV proteins and organelles. To obtain a better understanding of the various cytopathic effects of and cellular responses to HCV proteins, we used human hepatoma cells constitutively replicating HCV RNA encoding either the full-length polyprotein or the non-structural proteins, or cells constitutively expressing the structural protein core, to model the state of persistent HCV infection and examined the combination of various HCV proteins in cellular pathogenesis. Increased reactive oxygen species (ROS) generation in the mitochondria, mitochondrial injury and degeneration, and increased lipid accumulation were common among all HCV protein-expressing cells regardless of whether they expressed the structural or non-structural proteins. Expression of the non-structural proteins also led to increased oxidative stress in the cytosol, membrane blebbing in the endoplasmic reticulum, and accumulation of autophagocytic vacuoles. Alterations of cellular redox state, on the other hand, significantly changed the level of autophagy, suggesting a direct link between oxidative stress and HCV-mediated activation of autophagy. With the wide-spread cytopathic effects, cells with the full-length HCV polyprotein showed a modest antioxidant response and exhibited a significant increase in population doubling time and a concomitant decrease in cyclin D1. In contrast, cells expressing the non-structural proteins were able to launch a vigorous antioxidant response with up-regulation of antioxidant enzymes. The population doubling time and cyclin D1 level were also comparable to that of control cells. Finally, the cytopathic effects of core protein appeared to focus on the mitochondria without remarkable disturbances in the cytosol

The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository

Current understanding of chronic diseases is based on crude clinical characterization, imaging studies, and laboratory testing that has evolved over decades. The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study is a multi-tiered, longitudinal study designed to enable classification of chronic diseases using clinically annotated biospecimen collections, -omic technologies, electronic health records, and standard epidemiological methods. We expect that detailed molecular classification will improve mechanistic understanding of chronic diseases, augmenting discovery and testing of new treatments, and allowing refined selection of prevention and treatment strategies. The MURDOCK Study Community Registry and Biorepository will serve as a bridge for validation of initial exploratory studies, a platform for future prospective studies in targeted populations, and a resource of both data (analytical and clinical) and samples for cross-registry meta-analyses and comparative population studies. Participation of local health care providers and the Cabarrus County/Kannapolis, NC, community will facilitate future medical research and provide the opportunity to educate and inform the public about genomic research, actively engaging them in shaping the future of medical discovery and treatment of chronic diseases. We present the rationale and study design for the MURDOCK Community Registry and Biorepository and baseline characteristics of the first 6000 participants