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Open Access Highly Accessed Research article

A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

Cristian Pattaro1*, Alessandro De Grandi1, Veronique Vitart2, Caroline Hayward2, Andre Franke3, Yurii S Aulchenko4, Asa Johansson5, Sarah H Wild6, Scott A Melville1, Aaron Isaacs4, Ozren Polasek78, David Ellinghaus3, Ivana Kolcic7, Ute Nöthlings109, Lina Zgaga7, Tatijana Zemunik11, Carsten Gnewuch12, Stefan Schreiber3, Susan Campbell2, Nick Hastie2, Mladen Boban11, Thomas Meitinger1314, Ben A Oostra4, Peter Riegler15, Cosetta Minelli1, Alan F Wright2, Harry Campbell6, Cornelia M van Duijn4, Ulf Gyllensten5, James F Wilson6, Michael Krawczak169, Igor Rudan1168, Peter P Pramstaller11718* and the EUROSPAN consortium

Author Affiliations

1 Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University Lübeck, Lübeck, Germany

2 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK

3 Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany

4 Genetic Epidemiology Unit, Departments of Epidemiology and Clinical Genetics, Erasmus MC, 3000 CA Rotterdam, the Netherlands

5 Department of Genetics and Pathology, Rudbeck laboratory, Uppsala University, SE-751 85, Uppsala, Sweden

6 Centre for Population Health Sciences, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, UK

7 Andrija Stampar School of Public Health, University of Zagreb Medical School, Rockefellerova 4, 10000 Zagreb, Croatia

8 Gen-info Ltd, Ruzmarinka 17, 10000 Zagreb, Croatia

9 Popgen biobank, Christian-Albrechts-University Kiel, Kiel, Germany

10 Institute for Experimental Medicine, Christian-Albrechts University Kiel, 24105 Kiel, Germany

11 Croatian Centre for Global Health, University of Split Medical School, Soltanska 2, 21000 Split, Croatia

12 Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, D-93053 Regensburg, Germany

13 Institute of Human Genetics, Technical University of Munich, Munich, Germany

14 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr 1, D-85764 Neuherberg, Germany

15 Hemodialysis Unit, Hospital of Merano, Merano, Italy

16 Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel, Germany

17 Department of Neurology, University of Lübeck, Lübeck, Germany

18 Department of Neurology, Central Hospital, Bolzano, Italy

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BMC Medical Genetics 2010, 11:41  doi:10.1186/1471-2350-11-41

Published: 11 March 2010

Abstract

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.