TY - JOUR
T1 - A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level
AU - Pattaro, Cristian
AU - De Grandi, Alessandro
AU - Vitart, Veronique
AU - Hayward, Caroline
AU - Franke, Andre
AU - Aulchenko, Yurii S.
AU - Johansson, Asa
AU - Wild, Sarah H.
AU - Melville, Scott A.
AU - Isaacs, Aaron
AU - Polasek, Ozren
AU - Ellinghaus, David
AU - Kolcic, Ivana
AU - Nöthlings, Ute
AU - Zgaga, Lina
AU - Zemunik, Tatijana
AU - Gnewuch, Carsten
AU - Schreiber, Stefan
AU - Campbell, Susan
AU - Hastie, Nick
AU - Boban, Mladen
AU - Meitinger, Thomas
AU - Oostra, Ben A.
AU - Riegler, Peter
AU - Minelli, Cosetta
AU - Wright, Alan F.
AU - Campbell, Harry
AU - van Duijn, Cornelia M.
AU - Gyllensten, Ulf
AU - Wilson, James F.
AU - Krawczak, Michael
AU - Rudan, Igor
AU - Pramstaller, Peter P.
N1 - Funding Information:
We owe a debt of gratitude to all participants in the seven studies and their relatives. We are grateful to Prof. John Thompson for the very constructive discussion on statistical methodology. EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947). High-throughput genome-wide association analysis of the data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The ERF study was supported by grants from the NWO, Erasmus MC and the Centre for Medical Systems Biology (CMSB). We are grateful general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. For the MICROS study, we thank the primary care practitioners Raffaela Stocker, Stefan Waldner, Toni Pizzecco, Josef Plangger, Ugo Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation. The Northern Swedish Population Health Study was supported by grants from The Swedish Natural Sciences Research Council, The European Commission through EUROSPAN, The Foundation for Strategic Research (SSF) and The Linneaus Centre for Bioinformatics (LCB). We are also grateful for the contribution of samples from the Medical Biobank in Umeå and for the contribution of the district nurse Svea Hennix in the Karesuando study. ORCADES was supported by the Scottish Executive Health Department and the Royal Society. DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson, the research nurses in Orkney, and the administrative team in Edinburgh. The VIS study was supported through the grants from the Medical Research Council UK to HC, AFW and IR; and Ministry of Science, Education and Sport of the Republic of Croatia to IR (number 108-1080315-0302). The authors collectively thank a large number of individuals for their individual help in organizing, planning and carrying out the field work related to the project and data management: Professor Pavao Rudan and the staff of the Institute for Anthropological Research in Zagreb, Croatia (organization of the field work, anthropometric and physiological measurements, and DNA extraction); Professor Ariana Vorko-Jovic and the staff and medical students of the Andrija Stampar School of Public Health of the Faculty of Medicine, University of Zagreb, Croatia (questionnaires, genealogy reconstruction and data entry); Dr Branka Salzer from the biochemistry lab “Salzer”, Croatia (measurements of biochemical traits); local general practitioners and nurses (recruitment and communication with the study population); and the employees of several other Croatian institutions who participated in the field work, including but not limited to the University of Rijeka and Split, Croatia; Croatian Institute of Public Health; Institutes of Public Health in Split and Dubrovnik, Croatia. SNP Genotyping of the Vis samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, WGH, Edinburgh. The popgen study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN). It is currently funded by the Ministry of Science, Commerce and Transportation of the State of Schleswig-Holstein. The project has also received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces”.
PY - 2010/3/11
Y1 - 2010/3/11
N2 - 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 SCR level is explicable by genetic factors.Methods: We performed a meta-analysis of genome-wide association studies of SCR undertaken 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 SCR level 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 × 10-6 and 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 GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAAreceptors and synaptotagmin-I at the podocyte level.
AB - 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 SCR level is explicable by genetic factors.Methods: We performed a meta-analysis of genome-wide association studies of SCR undertaken 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 SCR level 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 × 10-6 and 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 GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAAreceptors and synaptotagmin-I at the podocyte level.
UR - http://www.scopus.com/inward/record.url?scp=77949425860&partnerID=8YFLogxK
U2 - 10.1186/1471-2350-11-41
DO - 10.1186/1471-2350-11-41
M3 - Article
C2 - 20222955
AN - SCOPUS:77949425860
SN - 1471-2350
VL - 11
JO - BMC Medical Genetics
JF - BMC Medical Genetics
IS - 1
M1 - 41
ER -