Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes

Yingchang Lu, Latchezar Dimitrov, Shyh Huei Chen, Lawrence F. Bielak, Joshua C. Bis, Mary F. Feitosa, Lingyi Lu, Maryam Kavousi, Laura M. Raffield, Albert V. Smith, Lihua Wang, Stefan Weiss, Jie Yao, Jiaxi Zhu, Elias F. Gudmundsson, Valborg Gudmundsdottir, Daniel Bos, Mohsen Ghanbari, M. Arfan Ikram, Shih Jen HwangKent D. Taylor, Matthew J. Budoff, Gauti K. Gíslason, Christopher J. O'Donnell, Ping An, Nora Franceschini, Barry I. Freedman, Yi Ping Fu, Xiuqing Guo, Gerardo Heiss, Sharon L.R. Kardia, James G. Wilson, Carl D. Langefeld, Ulf Schminke, André G. Uitterlinden, Leslie A. Lange, Patricia A. Peyser, Vilmundur G. Gudnason, Bruce M. Psaty, Jerome I. Rotter, Donald W. Bowden, Maggie C.Y. Ng*

*Corresponding author for this work

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Abstract

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. Results: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

Original languageEnglish
Article numberE003258
JournalCirculation: Genomic and Precision Medicine
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Aug 2021

Bibliographical note

Funding Information:
AA-DHS (African American-Diabetes Heart Study) was supported by the National Institutes of Health (NIH) R01 DK071891, NIH R01 AR48797, and NIH R01 HL67348. The AGES (Aging Gene-Environment Susceptibility-Reykjavik Study) has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute (NHLBI), NIH, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HH-SN268201700003I, HHSN268201700005I, HHSN268201700004I). The CHS (Cardiovascular Health Study) research was supported by the NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, N01HC85085, N01HC45133; and NHL-BI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114, and R01HL068986 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute (CTSI) grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The DHS (Diabetes Heart Study) research reported in this article was supported in part by R01 HL67348, R01 HL092301, R01 NS058700, R01 DK066358, and the General Clinical Research Centre of the Wake Forest School of Medicine (M01 RR07122, F32 HL085989). The FamHS (Family Heart Study) research was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from the NHLBI; and R01-DK-089256 from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK). The NHLBI’s FHS (Framingham Heart Study) is supported by contract N01-HC-25195. Support for GENOA (Genetic Epidemiology Network of Arteriopathy) was provided by the NHLBI (HL054457, HL054464, HL054481, HL119443, HL087660, and HL085571) of the NIH. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HH-SN268201800015I), and the University of Mississippi Medical Center (HH-SN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities (NIMHD). MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA SHARe (SNP Health Association Resource) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Geno-typing was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and Massachusetts Institute of Technology (MIT; Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Also supported in part by the NHLBI contracts R01HL151855 and R01HL146860. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the NIDDK DRC grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The generation and management of the Illumina exome chip v1.0 array data for the RS-I (Rotterdam Study) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810); the now (project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri. nl). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission Directorate-General for Science, Research and Development (DG XII), and the Municipality of Rotterdam. The SHIP (Study of Health in Pomerania) and SHIP-TREND are part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); 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). Dr Lu is supported by R56HL150186.

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