HL EL S267F, C-480T C-514T G-216A, C-480T, A-719G C-514T C-514T C-480T Thr111Ilea Thr111Ile Thr111Ile Thr111Ile 2879 cases and 7735 controls 501 1741 cases and 7948 controls 562 cases and 642 controls 496 cases and 294 controls 87 107 cases and 107 controls 265 cases and 265 controls 1501 cases and 2639 controls 607 cases and 1271 controls ND ND ND ND ND ND ND ND Decreased HL activity ND Impact on HDL cholesterol levels Increased ND Increased Increased Increased or not affected ND Not affected Increased Not affected Increased Outcome for atherosclerosis or CVD Reference No association with risk of ischemic CVD Increased coronary plaque area in carriers Increased risk of ischemic heart disease in homozygotes for all 3 variants Increased risk of cardiovascular heart disease in [23] male carriers but not in female carriers No association with risk of CVD [24] Increased carotid intima-media wall thickness in homozygous carriers Decreased risk of acute myocardial infarction in carriers Decreased risk of coronary artery disease in carriers No association with risk of coronary heart disease No association with risk of coronary artery disease [8] [21] [22] [25] [47] [48] [49] [50] Curr Atheroscler Rep (2011) 13:257–265 261 Table 2 Selected hepatic lipase and endothelial lipase gene polymorphisms and their association with atherosclerosis and cardiovascular disease Lipase Gene Number of polymorphism subjects Impact on lipase expression and activity CVD cardiovascular disease, HL hepatic lipase, EL endothelial lipase, ND not determined a Please note that functional studies indicated that the Thr111Ile variant of endothelial lipase does not differ in expression and activity from wild-type endothelial lipase [34 ] genotype of the C-480T variant, who have higher HL activity, had a 13% greater carotid intima wall-thickness [25]. Taken together, these data stress the need for further carefully conducted studies that, in addition to genotyping the participating subjects, also aim to correlate HL mass as well as activity with relevant hard clinical end points of atherosclerotic CVD. Endothelial Lipase EL, encoded by the LIPG gene, is a 68-kD glycoprotein that was cloned independently in 1999 by two groups (Table 1) [26, 27]. The amino acid sequence of EL is 41% homologous to HL. Nevertheless, EL is distinct from other members of the triacylglycerol family because it is synthe- sized and secreted by endothelial cells. In addition, expres- sion of EL has been detected in human placenta, thyroid gland, lung, liver, kidney, ovary, testis, and macrophages in vitro as well as in foam cells within human atherosclerotic plaques (Table 1) [3, 26, 27]. EL has primarily sn-1- phospholipase activity toward all lipoprotein subclasses, however, the preferred substrate is apparently phospholipids within HDL (Table 1) [3]. Similar to HL, EL mediates bridging between lipoproteins and cell surface heparin sulfate proteoglycans [3]. EL and HDL Metabolism EL is a negative regulator of plasma HDL cholesterol levels (Table 1). Adenovirus-mediated overexpression of EL resulted in a marked decrease in plasma HDL cholesterol and apoA-I levels due to a dose-dependent increase in the catabolic rate of HDL apolipoproteins as well as HDL-CE [27, 28 , 29]. These metabolic effects are almost entirely dependent on the catalytic activity of EL and are not so much mediated by its bridging function, as overexpression of catalytically inactive EL had discernable effects on plasma HDL cholesterol only in HL-deficient mice but not in wild-type or apoA-I transgenic mice [3]. Conversely, loss-of-function studies in mice using either specific EL knockout models or antibody-mediated EL inhibition showed increased plasma levels of phospholipids, apoA-I, and HDL cholesterol due to a slower catabolic rate [3, 6 ]. Also a shift in the HDL size toward larger particles was noted [3]. Interestingly, inhibition of EL activity [3] or EL knockout [6 ] in HL-deficient mice resulted in a further significant increase in plasma HDL cholesterol levels, indicating an independent and additive role of these lipases in HDL metabolism. Based on these experimental findings, we have proposed a model in which hydrolysis of HDL phospholipids by EL destabilizes the HDL particle, resulting in shedding of