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Zagreb, Croatia
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Sotoodehnia N.,University of Washington | Isaacs A.,Erasmus Medical Center | Isaacs A.,Center for Medical Systems Biology | De Bakker P.I.W.,Harvard University | And 141 more authors.
Nature Genetics | Year: 2010

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10 -8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction. © 2010 Nature America, Inc. All rights reserved.


Kilpelainen T.O.,Institute of Metabolic Science | Zillikens M.C.,Erasmus University Rotterdam | Zillikens M.C.,Sponsored Netherlands Consortium for Healthy Aging NCHA | Stancakova A.,Kuopio University Hospital | And 145 more authors.
Nature Genetics | Year: 2011

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10-6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10-26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10-11) and one near SPRY2 (P = 3 × 10-8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. © 2011 Nature America, Inc. All rights reserved.


Pattaro C.,European Academy Bozen Bolzano EURAC | Pattaro C.,University of Lübeck | De Grandi A.,European Academy Bozen Bolzano EURAC | Vitart V.,Institute of Genetics and Molecular Medicine | And 36 more authors.
BMC Medical Genetics | Year: 2010

Background: Serum creatinine (SCR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in SCRlevel is explicable by genetic factors.Methods: We performed a meta-analysis of genome-wide association studies of SCRundertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR(candidate loci) were replicated in two additional population-based samples ('replication cohorts').Results: After the discovery meta-analysis, 29 loci were selected for replication. Association between SCRlevel and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10-6and 1.7 × 10-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 × 10-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated.Conclusions: While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAAreceptors in the regulation of the glomerular basement membrane and a possible interaction between GABAAreceptors and synaptotagmin-I at the podocyte level. © 2010 Pattaro et al; licensee BioMed Central Ltd.


O'Dushlaine C.,Trinity College Dublin | McQuillan R.,University of Edinburgh | Weale M.E.,King's College London | Crouch D.J.M.,King's College London | And 21 more authors.
European Journal of Human Genetics | Year: 2010

The genetic structure of human populations is important in population genetics, forensics and medicine. Using genome-wide scans and individuals with all four grandparents born in the same settlement, we here demonstrate remarkable geographical structure across 8-30 km in three different parts of rural Europe. After excluding close kin and inbreeding, village of origin could still be predicted correctly on the basis of genetic data for 89-100% of individuals. © 2010 Macmillan Publishers Limited All rights reserved.


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.


Franklin C.S.,University of Edinburgh | Franklin C.S.,Wellcome Trust Sanger Institute | Aulchenko Y.S.,Erasmus Medical Center | Huffman J.E.,Western General Hospital | And 15 more authors.
Annals of Human Genetics | Year: 2010

Genome-wide association (GWA) studies have identified around 20 common genetic variants influencing the risk of type 2 diabetes (T2D). Likewise, a number of variants have been associated with diabetes-related quantitative glycaemic traits, but to date the overlap between these genes and variants has been low. The majority of genetic studies have focused on fasting plasma glucose levels; however, this measure is highly variable. We have conducted a GWA meta-analysis of glycated haemoglobin (HbA1C) levels within three healthy nondiabetic populations. This phenotype provides an estimate of mean glucose levels over 2-3 months and is a more stable predictor of future diabetes risk. Participants were from three isolated populations: the Orkney Isles in the north of Scotland, the Dalmatian islands of Vis, and Korčula in Croatia (total of 1782 nondiabetic subjects). Association was tested in each population and results combined by meta-analysis. The strongest association was with the TCF7L2 gene (rs7903146, P= 1.48 × 10-7). This is also the strongest common genetic risk factor for T2D but it has not been identified in previous genome-wide studies of glycated haemoglobin. © 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.


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.


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.

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