Regular paper Interleukin-6 genotype is associated with high-density lipoprotein cholesterol responses to exercise training Amy Halverstadt a, T , Dana A. Phares a , Stephen Roth a , Robert E. Ferrell b , Andrew P. Goldberg c , James M. Hagberg a a Department of Kinesiology, University of Maryland, College Park, MD 20742-2611, United States b Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, United States c Division of Gerontology, University of Maryland School of Medicine, and Geriatric Research, Education, and Clinical Center, VA Medical Center, Baltimore, MD 21201, United States Received 17 December 2004; received in revised form 4 March 2005; accepted 8 March 2005 Available online 24 March 2005 Abstract Background: High-density lipoprotein cholesterol (HDL-C) and its subfractions are modifiable with exercise training and these responses are heritable. The interleukin-6 (IL6)-174G/C polymorphism may be associated with HDL-C levels. We hypothesized that the IL6-174G/C polymorphism would be associated with plasma HDL-C response to exercise training. Methods and results: Sixty-five 50- to 75-year-olds on a standardized diet were studied before and after 24 weeks of aerobic exercise training. Significant differences existed among genotype groups for change with exercise training in HDL-C, HDL 3 -C, integrated HDL 4,5NMR -C, and HDL size . The CC genotype group increased HDL-C more than the GG (7.0 F 1.3 v. 1.0 F 1.1 mg/dL, p = 0.001) and GC groups (3.3 F 0.9 mg/dL, p = 0.02); for HDL 3 -C, the CC group increased more than the GG (6.1 F 1.0 v. 0.9 F 0.9, mg/dL p b 0.001) and GC groups (2.5 F 0.7 mg/dL, p = 0.006). Integrated HDL 4,5NMR -C increased more in the CC than GG group (6.5 F 1.6 mg/dL v. 1.0 F 1.3 mg/dL, p = 0.01), as did HDL size compared to the GG (CC: 0.3 F 0.1 v. GG: 0.1 F 0.1 nm, p = 0.02) and GC (0.0 F 0.0 nm, p = 0.007) groups. Conclusions: IL6 genotype is associated with HDL-C response to exercise training. D 2005 Elsevier B.V. All rights reserved. Keywords: Lipid; Lipoprotein; Genetic; Exercise; Risk factor 1. Introduction Cardiovascular (CV) disease is currently the leading cause of morbidity and mortality in the developed world and will soon be the most critical health problem across the globe [1]. For over 30 years, plasma lipoprotein-lipids have been known to be major physiological contributors to the pathophysiology of atherosclerotic vascular disease and have been classified as a major CV disease risk factor [1,2]. However, recent evidence suggests that chronic inflamma- tion, mediated by elevated levels of the inflammatory cytokine interleukin-6 (IL-6), is one underlying mechanism that regulates the atherosclerotic process [2–4]. Elevated IL-6 levels have been associated with many CV disease risk factors including obesity, diabetes, and dyslipidemia [5–7]. Endurance exercise training has been shown to reduce CV disease risk by improving CV disease risk profiles, including producing positive increases in high-density lipoprotein cholesterol (HDL-C) levels [8]. IL-6 and other inflammatory cytokines produce pro- atherogenic changes in lipid metabolism and lipoproteins that include alterations in the enzymes and apolipoproteins associated with HDL-C [9–11]. These enzymatic and structural changes may reduce HDL-C levels and impair HDL anti-inflammatory, anti-oxidant, and reverse choles- terol transport functions, thus inhibiting its normally protective role in CV disease prevention [9–11]. IL-6 inhibits adipose lipoprotein lipase and stimulates increased lipolysis, free fatty acid (FFA) levels, and secretion of 1388-1981/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2005.03.003 T Corresponding author. Tel.: +1 301 405 2571; fax: +1 301 405 5578. E-mail address: halveraa@aol.com (A. Halverstadt). Biochimica et Biophysica Acta 1734 (2005) 143 – 151 http://www.elsevier.com/locate/bba