@article{bd74284f5b0b416db9477f8820ba3848,
title = "Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies",
abstract = "Background and aims: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). Methods: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993. Results: Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048). Conclusion: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.",
keywords = "Coronary heart disease, Fetuin-A, Mendelian randomization, Meta-analysis, Single nucleotide polymorphisms",
author = "Laugsand, {Lars E.} and Ix, {Joachim H.} and Bartz, {Traci M.} and Luc Djousse and Kizer, {Jorge R.} and Tracy, {Russell P.} and Abbas Dehghan and Kathryn Rexrode and Lopez, {Oscar L.} and Rimm, {Eric B.} and Siscovick, {David S.} and O'Donnell, {Christopher J.} and Anne Newman and Mukamal, {Kenneth J.} and Jensen, {Majken K.}",
note = "Funding Information: The HPFS CHD case-control study was supported by HL35464, and CA55075 from the National Institutes of Health, Bethesda, MD, with additional support for genotyping from Merck/Rosetta Research Laboratories, North Wales, PA. NHS: The NHS CHD case-control study was supported by CA87969 and HL34594 from the National Institutes of Health, Bethesda, MD, with additional support for genotyping from Merck/Rosetta Research Laboratories, North Wales, PA. Funding Information: CHARGE cohorts: AGES study was funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ARIC is supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. FHS was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (N02-HL-6-4278). Abbas Dehghan is supported by Netherlands Organization for Scientific Research (NWO) grant (veni, 916.12.154) and the EUR Fellowship. Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. Health ABC was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). Funding Information: The manuscript was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) ( R01 HL094555 to LD, J.R.K. J.H.I, and K.J.M) and genotyping was funded by the NHLBI CARe project (Broad Institute of Massachusetts Institute of Technology and Harvard, N01HC65226 ). The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and NO1HC85086, and by grant HL080295 from NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A complete list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm . Lars E. Laugsand received a research fellowship grant from the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. Publisher Copyright: {\textcopyright} 2015 Elsevier Ireland Ltd. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",
year = "2015",
month = nov,
day = "1",
doi = "10.1016/j.atherosclerosis.2015.08.031",
language = "English (US)",
volume = "243",
pages = "44--52",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd",
number = "1",
}