Dear Sir, Low high-density lipoprotein cholesterol (HDL-C) is a strong risk factor for coronary artery disease (CAD). It is not clear, however, whether this also applies to individuals with Tangier disease (TD), who due to mutations in the ATP-binding cassette A1 (ABCA1) gene present with extremely low HDL-C. To illustrate this clinical enigma we present a novel TD patient who displays no symptoms of atherosclerosis at age 52. This individual is compared with an almost identical 38-year old TD patient who suffered a near-fatal myocardial infarction (MI). This letter discusses the paradox of HDL-C deficiency and absence of atherosclerosis in the context of ABCA1 dysfunction.

Tangier disease is a rare genetic disorder of lipid metabolism, characterized by a near absence of plasma HDL-C. Recently, mutations in the ABCA1 gene have been shown to cause TD [1–3]. Complete loss of ABCA1 function leads to severely decreased cellular cholesterol efflux and cholesteryl ester accumulation in macrophages and other cells of the reticuloendothelial system. Clinically, TD patients often present with hepatosplenomegaly, peripheral neuropathy, enlarged yellow tonsils and fatty deposits in the rectal mucosa. Earlier studies suggested that carriers of ABCA1 defects bear a moderately increased risk for CAD [4]. However, due to the small number of ABCA1 mutation carriers and a biased referral of the index patients, it was hitherto impossible to draw firm conclusions. To further address this issue, we previously investigated the association between ABCA1-mediated cholesterol efflux and intima media thickness (IMT) of the carotid arteries. We indeed found an inverse correlation between IMT and cholesterol efflux, suggesting that reduced ABCA1 function increases the risk for atherosclerosis in ABCA1 mutation carriers [5]. Recently,