A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level
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
BMC Medical Genetics 2010, 11:41 doi:10.1186/1471-2350-11-41Published: 11 March 2010
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.
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').
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.
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.