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Zagreb, Croatia

Knezevic A.,University of Zagreb | Gornik O.,University of Zagreb | Polasek O.,University of Zagreb | Pucic M.,Genos Ltd | And 10 more authors.
Glycobiology | Year: 2010

Protein glycosylation affects nearly all molecular interactions at the cell surface and in the intercellular space. Many of the physiological variations which are part of homeostatic mechanisms influence glycosylation. However, a comprehensive overview of changes in glycosylation caused by aging and common lifestyle parameters is still lacking. After analyzing N-glycans in the plasma of 1914 individuals from the Croatian islands of Vis and Korčula, we performed a comprehensive analysis of the dependence of different glycosylation features (position of fucose, level of galactosylation, sialylation and branching) on aging, smoking, body fat and plasma lipid status. A number of statistically significant associations were observed. Glycosylation changes with aging were especially evident in females, mostly in association with the transition from pre-menopausal to post-menopausal age. Levels of corefucosylated, non-galactosylated, digalactosylated and disialylated biantennary glycans were shown to be mainly age dependent, but the level of branching and higher levels of galactosylation were found to correlate with lipid status. For the majority of glycans which we analyzed, all examined parameters explained up to 5% of the variance. The only notable exception were non-galactosylated glycans where 20% of the variance was explained mostly by age and blood pressure. In general, only a small fraction of the variability in glycan levels observed in a population was explained by age and other measured parameters, indicating that even in the absence of a genetic template, glycan levels are mostly determined by genetic background and/or specific pathophysiological processes. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org. Source


Lauc G.,Genos Ltd | Lauc G.,University of Zagreb | Essafi A.,Western Research Institute | Huffman J.E.,Western Research Institute | And 27 more authors.
PLoS Genetics | Year: 2010

Over half of all proteins are glycosylated, and alterations in glycosylation have been observed in numerous physiological and pathological processes. Attached glycans significantly affect protein function; but, contrary to polypeptides, they are not directly encoded by genes, and the complex processes that regulate their assembly are poorly understood. A novel approach combining genome-wide association and high-throughput glycomics analysis of 2,705 individuals in three population cohorts showed that common variants in the Hepatocyte Nuclear Factor 1a (HNF1a) and fucosyltransferase genes FUT6 and FUT8 influence N-glycan levels in human plasma. We show that HNF1a and its downstream target HNF4a regulate the expression of key fucosyltransferase and fucose biosynthesis genes. Moreover, we show that HNF1a is both necessary and sufficient to drive the expression of these genes in hepatic cells. These results reveal a new role for HNF1a as a master transcriptional regulator of multiple stages in the fucosylation process. This mech anism has implications for theregulation of immunity, embryonic development, and protein folding, as well as for our understanding of the molecular mechanisms underlying cancer, coronary heart disease, and metabolic and inflammatory disorders. © 2010 Lauc et al. Source


Igl W.,Uppsala University | Polaek O.,University of Split | Gornik O.,University of Zagreb | Kneevic A.,Genos Ltd | And 15 more authors.
Molecular BioSystems | Year: 2011

Recently, high-throughput technologies have been made available which allow the measurement of a broad spectrum of glycomics and lipidomics parameters in many samples. The aim of this study was to apply these methods and investigate associations between 46 glycan and 183 lipid traits measured in blood of 2041 Europeans from three different local populations (Croatia - VIS cohort; Sweden - NSPHS cohort; Great Britain - ORCADES cohort). N-glycans have been analyzed with High Performance Liquid Chromatography (HPLC) and lipids with Electrospray Ionization Tandem Mass Spectrometry (ESI-MS/MS) covering sterol lipids, glycerolipids, glycerophospholipids and sphingolipids in eight subclasses. Overall, 8418 associations were calculated using linear mixed effect models adjusted for pedigree, sex, age and multiple testing. We found 330 significant correlations in VIS. Pearson's correlation coefficient r ranged from -0.27 to 0.34 with corresponding p-values between 1.45 × 10 -19 and 4.83 × 10 -6, indicating statistical significance. A total of 71 correlations in VIS could be replicated in NSPHS (r = [-0.19; 0.35], p = [4.16 × 10 -18; 9.38 × 10 -5]) and 31 correlations in VIS were also found in ORCADES (r = [-0.20; 0.24], p = [2.69 × 10 -10; 7.55 × 10 -5]). However, in total only 10 correlations between a subset of triantennary glycans and unsaturated phosphatidylcholine, saturated ceramide, and sphingomyelin lipids in VIS (r = [0.18; 0.34], p = [2.98 × 10 -21; 1.69 × 10 -06]) could be replicated in both NSPHS and ORCADES. In summary, the results show strong and consistent associations between certain glycans and lipids in all populations, but also population-specific correlations which may be caused by environmental and genetic differences. These associations point towards potential interactive metabolic pathways. © 2011 The Royal Society of Chemistry. Source


Lauc G.,University of Zagreb | Lauc G.,Genos Ltd | Rudan I.,Gen Information Ltd | Rudan I.,University of Split | And 3 more authors.
Molecular BioSystems | Year: 2010

One hundred years have passed since Archibald Garrod postulated the one gene/one enzyme hypothesis. Since then, science has made significant progress and geneticists are now tackling an overwhelming complexity of gene regulation networks that underlie the genetics of complex human diseases. A particularly complex element in the biology of higher organisms is the genetics of protein glycosylation. Nearly all proteins that appeared after the emergence of multicellular life are glycosylated, but instead of being molded by a single gene, glycan structures are encoded within a network of several hundred glycosyltransferases, glycosidases, transporters, transcription factors and other proteins. In addition, in contrast to the linear structures of DNA and proteins, glycans have multiple branches that make their analysis significantly more challenging. However, recent developments in high throughput HPLC analysis have advanced glycan analysis significantly and it is now possible to address questions about the complex genetics of protein glycosylation. In this review we present some preliminary insights into this fascinating field. © 2010 The Royal Society of Chemistry. Source


Pucic M.,Genos Ltd | Pinto S.,University of Zagreb | Novokmet M.,Genos Ltd | Knezevic A.,University of Zagreb | And 12 more authors.
Glycobiology | Year: 2010

After performing hydrophilic interaction and weak anion exchange high-performance liquid chromatography to analyze N-glycans in the plasma of 1991 people, we identified several individuals that differed significantly from the "normal" profile of N-glycans. By performing consensus scoring of pairwise distances between vectors containing measured glycan values, we formed six groups of individuals with specific glyco-phenotypes. Some aberrations from the normal plasma protein patterns were found to be associated with clinical conditions (such as renal problems in people with increased monosialylated biantennary glycans, A2G2S1), while other substantial changes in N-glycan structure, such as the near complete absence of neutral glycans or antennary fucosylated tri-and tetraantennary glycans, were not associated with any observed adverse health outcomes. These results demonstrate the existence of specific altered glyco-phenotypes in some individuals and indicate that in some cases they might represent risk factors for the development of specific diseases. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org. Source

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