Project description:MicroRNAs (miRNAs) are single-stranded sequences of non-coding RNA with approximately 22 nucleotides that act posttranscriptionally on gene expression. miRNAs are important gene regulators in physiological contexts, but they also impact the pathogenesis of various diseases. The role of miRNAs in viral infections has been explored by different authors in both population-based as well as in functional studies. However, the effect of miRNA polymorphisms on the susceptibility to viral infections and on the clinical course of these diseases is still an emerging topic. Thus, this review will compile and organize the findings described in studies that evaluated the effects of genetic variations on miRNA genes and on their binding sites, in the context of human viral diseases. In addition to discussing the basic aspects of miRNAs biology, we will cover the studies that investigated miRNA polymorphisms in infections caused by hepatitis B virus, hepatitis C virus, human immunodeficiency virus, Epstein-Barr virus, and human papillomavirus. Finally, emerging topics concerning the importance of miRNA genetic variants will be presented, focusing on the context of viral infectious diseases.
Project description:In humans, the important water soluble, vitamin-like nutrient choline, is taken up with the diet or recycled in the liver. Deficiencies of choline have only been reported in experimental situations or total parenteral nutrition. Currently, no recommended dietary allowances are published; only an adequate daily intake is defined. Choline is involved in three main physiological processes: structural integrity and lipid-derived signaling for cell membranes, cholinergic neurotransmission, and methylation. Choline is gaining increasing public attention due to studies reporting a relation of low choline levels to subclinical organ dysfunction (nonalcoholic fatty liver or muscle damage), stunting, and neural tube defects. Furthermore, positive effects on memory and a lowering of cardiovascular risks and inflammatory markers have been proposed. On the other hand, dietary choline has been associated with increased atherosclerosis in mice. This mini review will provide a summary of the biochemical pathways, in which choline is involved and their respective inborn errors of metabolism (caused by mutations in SLC5A7, CHAT, SLC44A1, CHKB, PCYT1A, CEPT1, CAD; DHODH, UMPS, FMO3, DMGDH, and GNMT). The broad phenotypic spectrum ranging from malodor, intellectual disability, to epilepsy, anemia, or congenital myasthenic syndrome is presented, highlighting the central role of choline within human metabolism.
Project description:Toll-like receptors (TLRs) are germ-line-encoded innate immune sensors that recognize conserved microbial structures and host alarmins and signal expression of MHC proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These processes activate immediate and early mechanisms of innate host defense, as well as initiate and orchestrate adaptive immune responses. Several single-nucleotide polymorphisms (SNPs) within the TLR genes have been associated with altered susceptibility to infectious, inflammatory, and allergic diseases, and have been found to play a role in tumorigenesis. Critical advances in our understanding of innate immune functions and genome-wide association studies (GWAS) have uncovered complex interactions of genetic polymorphisms within TLRs and environmental factors. However, conclusions obtained in the course of such analyses are restricted by limited power of many studies that is likely to explain controversial findings. Further, linkages to certain ethnic backgrounds, gender, and the presence of multigenic effects further complicate the interpretations of how the TLR SNPs affect immune responses. For many TLRs, the molecular mechanisms by which SNPs impact receptor functions remain unknown. In this review, I have summarized current knowledge about the TLR polymorphisms, their impact on TLR signaling, and associations with various inflammatory, infectious, allergic diseases and cancers, and discussed the directions of future scientific research.
Project description:Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
Project description:Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.