Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus

Matthias Munz; Gesa M. Richter; Bruno G. Loos; Søren Jepsen; Kimon Divaris; Steven Offenbacher; Alexander Teumer; Birte Holtfreter; Thomas Kocher; Corinna Bruckmann; Yvonne Jockel-Schneider; Christian Graetz; Loreto Munoz; Anita Bhandari; Stephanie Tennstedt; Ingmar Staufenbiel; Nathalie van der Velde; André G. Uitterlinden; Lisette C.P.G.M. de Groot; Jürgen Wellmann; Klaus Berger; Bastian Krone; Per Hoffmann; Matthias Laudes; Wolfgang Lieb; Andre Franke; Henrik Dommisch; Jeanette Erdmann; Arne S. Schaefer

doi:10.1038/s41598-018-31980-8

Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus

Matthias Munz, Gesa M. Richter, Bruno G. Loos, Søren Jepsen, Kimon Divaris, Steven Offenbacher, Alexander Teumer, Birte Holtfreter, Thomas Kocher, Corinna Bruckmann, Yvonne Jockel-Schneider, Christian Graetz, Loreto Munoz, Anita Bhandari, Stephanie Tennstedt, Ingmar Staufenbiel, Nathalie van der Velde, André G. Uitterlinden, Lisette C.P.G.M. de Groot, Jürgen WellmannKlaus Berger, Bastian Krone, Per Hoffmann, Matthias Laudes, Wolfgang Lieb, Andre Franke, Henrik Dommisch, Jeanette Erdmann, Arne S. Schaefer^*

^*Corresponding author for this work

43 Citations (Scopus)

Abstract

Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (P_AgP-Ger < 0.05; P_CAD < 5 × 10⁻⁸; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.

Original language	English
Article number	13678
Journal	Scientific Reports
Volume	8
Issue number	1
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-018-31980-8
Publication status	Published - 01.12.2018

Funding

Data on coronary artery disease have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG. This work was supported by a research grant of the German Research Foundation DFG (Deutsche Forschungsgemeinschaft; G.Z.: SCHA 1582/3-1). Funding was provided by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed and sysINFLAME), the FP7 European Union project CVgenes@target (261123) and a grant from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02. This study was also supported through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. Collection of the AgP cases was additionally supported by the German Ministry of Education and Research through the POPGEN biobank project (01GR0468 and 01EY1103). The Dortmund Health Study (DHS) is supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Almirall, Astra Zeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp & Dohme and Pfizer to the University of Muenster (collection of sociodemographic and clinical data). Blood collection in the Dortmund Health Study was done through funds from the Institute of Epidemiology and Social Medicine University of Muenster and genotyping supported by the German Ministry of Research and Education (BMBF, Grant No. 01ER0816). FOCUS was supported by the Federal Ministry of Education and Research BMBF (FKZ 0315540A). The HNR study is supported by the Heinz Nixdorf Foundation (Germany). Additionally, the HNR study was funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1). The genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects was financed by the German Centre for Neurodegenerative Diseases (DZNE), Bonn. SHIP is part of the Community Medicine Research net (CMR, http://www.community-medicine.de) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants No. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). This project was granted by BMBF-01-ZZ-9603/0 and BH was supported by GABA, Switzerland. Generation of genome-wide SNP data has been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 5 Gender Equality

Research Areas and Centers

Research Area: Medical Genetics

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10.1038/s41598-018-31980-8

Cite this

Munz, M., Richter, G. M., Loos, B. G., Jepsen, S., Divaris, K., Offenbacher, S., Teumer, A., Holtfreter, B., Kocher, T., Bruckmann, C., Jockel-Schneider, Y., Graetz, C., Munoz, L., Bhandari, A., Tennstedt, S., Staufenbiel, I., van der Velde, N., Uitterlinden, A. G., de Groot, L. C. P. G. M., ... Schaefer, A. S. (2018). Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus. Scientific Reports, 8(1), Article 13678. https://doi.org/10.1038/s41598-018-31980-8

@article{da67f3223d4f43e888c8ff9479292174,

title = "Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus",

abstract = "Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10−8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95\% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95\% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.",

author = "Matthias Munz and Richter, \{Gesa M.\} and Loos, \{Bruno G.\} and S{\o}ren Jepsen and Kimon Divaris and Steven Offenbacher and Alexander Teumer and Birte Holtfreter and Thomas Kocher and Corinna Bruckmann and Yvonne Jockel-Schneider and Christian Graetz and Loreto Munoz and Anita Bhandari and Stephanie Tennstedt and Ingmar Staufenbiel and \{van der Velde\}, Nathalie and Uitterlinden, \{Andr{\'e} G.\} and \{de Groot\}, \{Lisette C.P.G.M.\} and J{\"u}rgen Wellmann and Klaus Berger and Bastian Krone and Per Hoffmann and Matthias Laudes and Wolfgang Lieb and Andre Franke and Henrik Dommisch and Jeanette Erdmann and Schaefer, \{Arne S.\}",

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doi = "10.1038/s41598-018-31980-8",

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Munz, M, Richter, GM, Loos, BG, Jepsen, S, Divaris, K, Offenbacher, S, Teumer, A, Holtfreter, B, Kocher, T, Bruckmann, C, Jockel-Schneider, Y, Graetz, C, Munoz, L, Bhandari, A, Tennstedt, S, Staufenbiel, I, van der Velde, N, Uitterlinden, AG, de Groot, LCPGM, Wellmann, J, Berger, K, Krone, B, Hoffmann, P, Laudes, M, Lieb, W, Franke, A, Dommisch, H, Erdmann, J & Schaefer, AS 2018, 'Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus', Scientific Reports, vol. 8, no. 1, 13678. https://doi.org/10.1038/s41598-018-31980-8

TY - JOUR

T1 - Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus

AU - Munz, Matthias

AU - Richter, Gesa M.

AU - Loos, Bruno G.

AU - Jepsen, Søren

AU - Divaris, Kimon

AU - Offenbacher, Steven

AU - Teumer, Alexander

AU - Holtfreter, Birte

AU - Kocher, Thomas

AU - Bruckmann, Corinna

AU - Jockel-Schneider, Yvonne

AU - Graetz, Christian

AU - Munoz, Loreto

AU - Bhandari, Anita

AU - Tennstedt, Stephanie

AU - Staufenbiel, Ingmar

AU - van der Velde, Nathalie

AU - Uitterlinden, André G.

AU - de Groot, Lisette C.P.G.M.

AU - Wellmann, Jürgen

AU - Berger, Klaus

AU - Krone, Bastian

AU - Hoffmann, Per

AU - Laudes, Matthias

AU - Lieb, Wolfgang

AU - Franke, Andre

AU - Dommisch, Henrik

AU - Erdmann, Jeanette

AU - Schaefer, Arne S.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10−8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.

AB - Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10−8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.

UR - https://www.scopus.com/pages/publications/85053284074

U2 - 10.1038/s41598-018-31980-8

DO - 10.1038/s41598-018-31980-8

M3 - Journal articles

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AN - SCOPUS:85053284074

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 13678

ER -

Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus

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Genome-wide Association Study for the Identification of Genetic Risk Factors of Periodontitis

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Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus

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Genome-wide Association Study for the Identification of Genetic Risk Factors of Periodontitis

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