Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Foam cell formation due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis. Macrophages cannot limit the uptake of cholesterol and therefore depend on cholesterol efflux pathways for preventing their transformation into foam cells. Several ABC-transporters, including ABCA1 and ABCG1, facilitate the efflux of cholesterol from macrophages. These transporters, however, also affect membrane lipid asymmetry which may have important implications for cellular endocytotic pathways. We propose that in addition to the generally accepted role of these ABC-transporters in the prevention of foam cell formation by induction of cholesterol efflux from macrophages, they also influence the macrophage endocytotic uptake.

Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein. Objective:The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis. ABCA1 is a full-size ABC-transporter that facilitates cholesterol efflux to lipid-poor apolipoprotein (apo)AI. 2,3 Totalbody ABCA1 knockout mice and Tangier disease patients with dysfunctional ABCA1 display a virtual absence of high-density lipoprotein (HDL), showing the essential role for ABCA1 in HDL metabolism. 3 Targeted inactivation of ABCA1 in bone marrow-derived cells in mice leads to increased atherosclerotic lesion formation, 4,5 whereas overexpression of ABCA1 inhibits the progression of atherosclerosis. 6 Macrophages lacking ABCA1, however, still have substantial ability to efflux cholesterol to HDL despite impaired efflux to lipid-poor apoAI, suggesting that macrophages have additional pathways via which cellular cholesterol can be exported. In addition to ABCA1, macrophages also express the ABC half-transporter ABCG1. In contrast to ABCA1, ABCG1 facilitates cellular cholesterol efflux from macrophages to mature HDL but not to lipid-free apolipopro- Methods and Results: