-Glutamyltransferase as a Risk Factor for Cardiovascular Disease Mortality An Epidemiological Investigation in a Cohort of 163 944 Austrian Adults Elfriede Ruttmann, MD; Larry J. Brant, PhD; Hans Concin, MD; Günter Diem, MD; Kilian Rapp, MD; Hanno Ulmer, PhD; and the Vorarlberg Health Monitoring and Promotion Program Study Group Background—There is evidence from recent studies that -glutamyltransferase (GGT) is likely to be associated with cardiovascular disease (CVD). However, few studies to date with sufficient sample size and follow-up investigated the association of GGT with CVD mortality. Methods and Results—The relation of GGT to the risk of death from CVD was examined in a cohort of 163 944 Austrian adults that was monitored for up to 17 years. To evaluate GGT as an independent predictor, Cox proportional hazards models were calculated, which adjusted for established risk factors. In both men and women, high GGT was significantly (P0.001) associated with total mortality from CVD, showing a clear dose-response relationship. Adjusted hazard ratios (95% CI) per log GGT increase were 1.66 (1.40 to 1.98) in men and 1.64 (1.36 to 1.97) in women. In men, subgroup analyses showed that high GGT was positively associated with incident fatal events of chronic forms of coronary heart disease (P=0.009), congestive heart failure (P0.001), and hemorrhagic (P=0.01) and ischemic stroke (P0.001). No significant associations were observed for acute myocardial infarction (P=0.16). In women, hazard ratios suggested associations in all subgroups; however, for hemorrhagic and ischemic stroke they were not statistically significant (P=0.09 and P=0.07, respectively). In addition, subgroup analyses stratified by age revealed a stronger relationship of GGT in younger participants. Hazard ratios for total CVD were 2.03 (1.53 to 2.69) in men and 2.60 (1.53 to 4.42) in women younger than 60 years. Conclusions—This study demonstrates in a large, prospectively observed cohort that GGT is independently associated with cardiovascular mortality. (Circulation. 2005;112:2130-2137.) Key Words: arteriosclerosis  cardiovascular diseases  prevention  risk factors  gamma-glutamyltransferase I n clinical practice, -glutamyltransferase (GGT) is a com- monly used diagnostic test. Although GGT is mainly seen as an indicator for liver function and alcohol consumption, several studies showed that it is associated with morbidity and mortality from causes other than liver disease, including cardiovascular disease (CVD). 1 In regard to coronary heart disease, it was observed that serum GGT levels were associ- ated with increased risk of myocardial infarction and cardiac death. 2–5 More recently, associations with stroke were report- ed. 6,7 However, such reports are rare, and consistent evidence is lacking because of the limited number of performed studies. Editorial p 2078 Although there is no doubt about the use of GGT as a monitor of liver function, there are now indications of GGT having a direct involvement in atherosclerotic plaque forma- tion. 8 GGT, present in serum and on the surface of most cell types, is the enzyme responsible for the extracellular catab- olism of glutathione, the main antioxidant in mammalian cells, and its role in CVDs may be more complex than is currently thought. 9 The possible role of GGT in the athero- sclerotic process suggests that its predictive value is at least partly independent of self-reported alcohol consumption. On the other hand, alcohol consumption has been recently confirmed to have a protective effect against myocardial infarction. 10 The Vorarlberg Health Monitoring and Promotion Program (VHM&PP), located in western Austria, is one of the world’s largest ongoing population-based risk factor surveillance programs. 11 Since 1985, approximately two thirds of the adult population in the region have been examined, and the database currently includes information from health exami- nations of 166 547 men and women. From the outset, mea- Received March 29, 2005; revision received June 23, 2005; accepted June 24, 2005. From the Department of Medical Statistics, Informatics, and Health Economics, Innsbruck Medical University, Innsbruck, Austria (E.R., H.U.); Gerontology Research Center, National Institute on Aging, Baltimore, Md (L.J.B.); Agency for Preventive and Social Medicine, Bregenz, Austria (H.C., G.D., H.U.); and Department of Epidemiology, University of Ulm, Ulm, Germany (K.R.). Correspondence to Hanno Ulmer, PhD, Department of Medical Statistics, Informatics, and Health Economics, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria. E-mail hanno.ulmer@uibk.ac.at © 2005 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.552547 2130 Epidemiology by guest on November 2, 2015 http://circ.ahajournals.org/ Downloaded from