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

M. Munz; G.M. Richter; B.G. Loos; S. Jepsen; K. Divaris; S. Offenbacher; A. Teumer; B. Holtfreter; T. Kocher; C. Bruckmann; Y. Jockel-Schneider; C. Graetz; L. Munoz; A. Bhandari; S. Tennstedt; I. Staufenbiel; N. van der Velde; A.G. Uitterlinden; L.C.P.G.M. de Groot; J. Wellmann; K. Berger; B. Krone; P. Hoffmann; M. Laudes; W. Lieb; A. Franke; H. Dommisch; J. Erdmann; A.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

M. Munz
, G.M. Richter
, B.G. Loos
, S. Jepsen
, K. Divaris
, S. Offenbacher
, A. Teumer
, B. Holtfreter
, T. Kocher
, C. Bruckmann
, Y. Jockel-Schneider
, C. Graetz
, L. Munoz
, A. Bhandari
, S. Tennstedt
, I. Staufenbiel
, N. van der Velde
, A.G. Uitterlinden
, L.C.P.G.M. de Groot
, J. Wellmann

K. Berger, B. Krone, P. Hoffmann, M. Laudes, W. Lieb, A. Franke, H. Dommisch, J. Erdmann, A.S. Schaefer

Periodontology

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	13678
Number of pages	10
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-31980-8
Publication status	Published - 12 Sept 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.

Funders	Funder number
FP7 European Union
University of Muenster
Universität Greifswald
Heinz Nixdorf Stiftung
Deutsches Zentrum für Neurodegenerative Erkrankungen
Federal State of Mecklenburg
Deutsche Migräne- und Kopfschmerzgesellschaft e.V.
European Commission
Wellcome Trust
Merck Sharp and Dohme
Ministry of Cultural Affairs
German Migraine & Headache Society
Fondation Leducq
Pfizer
Institute of Epidemiology and Social Medicine University of Muenster
Federal State of Mecklenburg-West Pomerania	03IS2061A, BMBF-01-ZZ-9603/0
CADgenomics: Understanding Coronary Artery Disease Genes	12CVD02
Seventh Framework Programme	261123
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	10388
Federal Ministry of Education and Research BMBF	FKZ 0315540A
Bundesministerium für Bildung und Forschung	01ZZ0403, 01GR0468, 01ER0816, 01EY1103, 01ZZ0103, 01ZZ9603
Deutsche Forschungsgemeinschaft	SCHA 1582/3-1, ER 155/6-1, SI 236/8-1, SI236/9-1
GABA	03ZIK012

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https://hdl.handle.net/11245.1/0d46c9a2-91de-43cd-88d4-a1fa0818e5be

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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

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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 = "M. Munz and G.M. Richter and B.G. Loos and S. Jepsen and K. Divaris and S. Offenbacher and A. Teumer and B. Holtfreter and T. Kocher and C. Bruckmann and Y. Jockel-Schneider and C. Graetz and L. Munoz and A. Bhandari and S. Tennstedt and I. Staufenbiel and \{van der Velde\}, N. and A.G. Uitterlinden and \{de Groot\}, L.C.P.G.M. and J. Wellmann and K. Berger and B. Krone and P. Hoffmann and M. Laudes and W. Lieb and A. Franke and H. Dommisch and J. Erdmann and A.S. Schaefer",

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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

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

AU - Munz, M.

AU - Richter, G.M.

AU - Loos, B.G.

AU - Jepsen, S.

AU - Divaris, K.

AU - Offenbacher, S.

AU - Teumer, A.

AU - Holtfreter, B.

AU - Kocher, T.

AU - Bruckmann, C.

AU - Jockel-Schneider, Y.

AU - Graetz, C.

AU - Munoz, L.

AU - Bhandari, A.

AU - Tennstedt, S.

AU - Staufenbiel, I.

AU - van der Velde, N.

AU - Uitterlinden, A.G.

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

AU - Wellmann, J.

AU - Berger, K.

AU - Krone, B.

AU - Hoffmann, P.

AU - Laudes, M.

AU - Lieb, W.

AU - Franke, A.

AU - Dommisch, H.

AU - Erdmann, J.

AU - Schaefer, A.S.

PY - 2018/9/12

Y1 - 2018/9/12

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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.

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U2 - 10.1038/s41598-018-31980-8

DO - 10.1038/s41598-018-31980-8

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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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