Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin

Anke Tönjes; Markus Scholz; Jana Breitfeld; Carola Marzi; Harald Grallert; Arnd Gross; Claes Ladenvall; Dorit Schleinitz; Kerstin Krause; Holger Kirsten; Esa Laurila; Jennifer Kriebel; Barbara Thorand; Wolfgang Rathmann; Leif Groop; Inga Prokopenko; Bo Isomaa; Frank Beutner; Jürgen Kratzsch; Joachim Thiery; Mathias Fasshauer; Nora Klöting; Christian Gieger; Matthias Blüher; Michael Stumvoll; Peter Kovacs

doi:10.1371/journal.pgen.1004854

Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin

PLoS Genet. 2014 Dec 18;10(12):e1004854. doi: 10.1371/journal.pgen.1004854. eCollection 2014 Dec.

Authors

Anke Tönjes¹, Markus Scholz², Jana Breitfeld³, Carola Marzi⁴, Harald Grallert⁴, Arnd Gross², Claes Ladenvall⁵, Dorit Schleinitz¹, Kerstin Krause¹, Holger Kirsten⁶, Esa Laurila⁵, Jennifer Kriebel⁷, Barbara Thorand⁸, Wolfgang Rathmann⁹, Leif Groop⁵, Inga Prokopenko¹⁰, Bo Isomaa¹¹, Frank Beutner¹², Jürgen Kratzsch¹², Joachim Thiery¹², Mathias Fasshauer¹³, Nora Klöting¹³, Christian Gieger¹⁴, Matthias Blüher¹³, Michael Stumvoll¹³, Peter Kovacs³

Affiliations

¹ Department of Medicine, University of Leipzig, Leipzig, Germany.
² Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE Research Center, University of Leipzig, Leipzig, Germany.
³ IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
⁴ Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
⁵ Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö, Sweden.
⁶ Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE Research Center, University of Leipzig, Leipzig, Germany; Department for Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
⁷ Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
⁸ Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany.
⁹ Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁰ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Department of Genomics of Common Diseases, Imperial College London, London, United Kingdom.
¹¹ Department of Social Services and Health Care, Jakobstad, Finland; Folkhälsan Research Centre, Helsinki, Finland.
¹² Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
¹³ Department of Medicine, University of Leipzig, Leipzig, Germany; IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
¹⁴ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Abstract

Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0×10-8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8×10-14, beta = -0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Chemokines / blood*
Chemokines / genetics*
Chemokines / metabolism
Gene Expression
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Intercellular Signaling Peptides and Proteins / blood*
Intercellular Signaling Peptides and Proteins / genetics*
Intercellular Signaling Peptides and Proteins / metabolism
Intra-Abdominal Fat / metabolism
Obesity / blood
Obesity / genetics
Polymorphism, Single Nucleotide
Subcutaneous Fat / metabolism

Substances

Chemokines
Intercellular Signaling Peptides and Proteins
RARRES2 protein, human

Grants and funding

Sorbs: This work was supported by grants from the German Research Council (SFB-1052 “Obesity mechanisms” B01, B03, B04, C01; SPP 1629 TO 718/2-1), from the German Diabetes Association and from the DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland). IFB Adiposity Diseases is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001. AG, HK and MSc were funded by the Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universität Leipzig). LIFE is funded by the European Union, by the European Regional Development Fund (ERFD), the European Social Fund and by the Free State of Saxony within the framework of the excellence initiative. KORA: The KORA research platform was initiated and financed by the Helmholtz Center Munich, and by the German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. This study was also supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study: The PPP–Botnia study in Finland was financially supported by grants from the Sigrid Juselius Foundation, the Folkhälsan Research Foundation, the Signe and Ane Gyllenberg Foundation, the Finnish Diabetes Research Foundation, the Foundation for Life and Health in Finland, the Finnish Medical Society, the Ollqvist Foundation and the Närpes Health Care Foundation. Funding has also been received in Sweden from the Swedish Research Council, including a Linné grant (No. 31475113580), and the Wallenberg Foundation. The DGI GWAS was carried out in collaboration with the Broad Institute and Novartis and funded by a grant from Novartis Pharma. The analyses performed at Lund University were supported by grants from the Swedish Research Council, including a Linnaeus Centre of Excellence grant (Dnr 2006-237) and a project grant (Dnr 2010-3490) to LG. Leipzig cohort: This work was supported by the Kompetenznetz Adipositas (Competence network for Obesity) funded by the Federal Ministry of Education and Research (German Obesity Biomaterial Bank; FKZ 01GI1128), and also by a grant from Deutsche Forschungsgemeinschaft (the SFB 1052 “Obesity mechanisms”). DS is funded by the Boehringer Ingelheim Foundation. LIFE Heart Study: The LIFE-Heart study was funded by LIFE – Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.