HDL deficiency and atherosclerosis: lessons from Tangier disease

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, studies with ABCA1 knockout mice confirmed our observations, and in further support, overexpression of ABCA1 has been shown to protect against diet-induced atherosclerosis [6]. We here describe a patient (case 1) whose clinical presentation supports the idea that loss of ABCA1 function is associated with premature atherosclerosis. A second novel TD patient, however, illustrates that severely reduced ABCA1 function does not always confer high CAD risk. Case 1: During jogging his daily 5 km, a 38-year-old nonsmoking, lean male [body mass index (BMI): 26] suddenly lost consciousness due to ventricular fibrillation. Subsequent defibrillation restored sinus rhythm and circulation; electrocardiogram revealed ST segment elevation, indicative of MI. Coronary angiography showed severe atherosclerosis of all coronary arteries (stenosis up to 80%) whilst, upon bypass surgery, the cardiothoracic surgeon noticed exceptional atherosclerosis of both mammary arteries. CAD risk factor analysis was unremarkable except for a striking dyslipidaemia, characterized by the near absence of HDL-C (<0.1 mmol L−1). At physical examination, splenomegaly, corneal opacities, peripheral neuropathy and absence of pulsations in the arteriae dorsales pedis were noted. His medical history was significant for tonsillectomy and a false diagnosis of Marie–Charcot–Tooth disease in adolescence. TD was suspected upon referral and his family was used in the search for the genetic cause of TD in 1999. This patient proved to be compound heterozygous for two ABCA1 gene mutations: a splicing defect (ivs 25+IG->C) and a missense mutation (C1477R). In line with these findings, ABCA1-mediated cholesterol efflux from his skin fibroblasts was severely reduced by 90% (compared with control). Case 2: A healthy 52-year-old man (BMI: 27) was referred because of HDL-C deficiency (<0.1 mmol L−1) at routine medical examination. No signs of atherosclerosis were noticed during physical examination whilst his family history was negative for CAD. After the discovery of the ABCA1 gene, his fibroblasts were cultured and cholesterol efflux tests revealed a 70% reduced ABCA1 function. This patient was compound heterozygous for a non-sense mutation (GG5277,8C) and a de novo missense mutation (T929I; confirmed upon paternity testing). A search for TD stigmata was unsuccessful; none were present, until sigmoidoscopy showed an abnormal mucosa, which is typical for TD. Intima media thickness measurements underscore the remarkable difference in (cardio)vascular disease status of these two cases. The presence of extraordinary wall thickening is observed in case 1, whilst in contrast the thickening of the vessel wall in case 2 is normal for an individual of his age (see Table 1). Tangier disease patients are relatively protected from atherosclerosis as they usually present with low levels of atherogenic low-density lipoprotein cholesterol (LDL-C) [7]. Case 2, however, seems to refute this idea because his LDL-C is normal instead of reduced (see Table 1). Furthermore, cholesterol ester transfer protein (CETP) concentrations are high in this patient, which can be considered as proatherogenic. Importantly, the difference in (cardio)vascular presentation in these two patients cannot be explained by differences in traditional CAD risk factors (i.e. elevated LDL-C, cigarette smoking, diabetes, hypertension, homocystein, fibrinogen or obesity). Further studies revealed that the 20% difference in cholesterol efflux between the two cases could not solely be attributed to differences in protein expression; Western blots of cultured fibroblasts revealed similar ABCA1 protein concentrations in both men. One can therefore conclude that the missense mutation in case 2 has a less severe effect on ABCA1 efflux capacity than the defect in case 1. It might therefore be hypothesized that further reduction of cholesterol efflux (from 90 to 70%) underlies the differences in phenotypes between case 1 and 2. Indeed, cellular cholesterol efflux studies show that severe cholesterol ester accumulation only occurs when ABCA1 function is almost fully inhibited. Obviously, humans can withstand considerable loss of ABCA1 function before severe premature atherosclerosis develops. The remarkable difference in (cardio)vascular disease status of these TD patients, who both suffer from severely reduced cellular cholesterol efflux due to compound heterozygosity for ABCA1 mutations, illustrates that impaired ABCA1-mediated efflux by itself is not always a prerequisite for enhanced atherosclerosis development. Our data suggest that HDL-C levels alone cannot be used to predict individual CAD risk in TD patients. No conflict of interest was declared.

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