GENOTYPE AND PHENOTYPE OF SUBJECTS WITH TANGIER DISEASE DEVELOPING CARDIOVASCULAR DISEASE

Objective: Tangier Disease (TD) is a rare inherited disorder that disrupts high-density lipoprotein (HDL) metabolism due to loss-of-function variants in the ATP-binding cassette subfamily A member 1 (ABCA1) gene. TD patients exhibit diverse clinical presentations, with only some individuals developing cardiovascular disease (CVD) despite extremely low HDL levels. To date, no detailed analyses have explored the genetic and phenotypic markers predicting cardiovascular complications in TD patients. This study aims to identify specific traits distinguishing TD patients prone to CVD. Materials and Methods: We reviewed all documented TD cases with a genetic diagnosis and constructed a clinical and genetic database using terms from the Human Phenotype Ontology database. Results: Among 73 TD patients with genetic diagnoses reported in the literature, 30 (41%) experienced CVD, while 43 (59%) did not. Patients with CVD exhibited recurring ABCA1 variants (n=25), absent in those without complications. These variants also showed distinct distributions across ABCA1 protein domains (X²=6.0685, p=0.04). Demographic and clinical features strongly associated with cardiovascular risk included older age (53 ± 10 years vs. 45 ± 15 years, p=0.04), orange-colored tonsils (X²=10.374, p=0.001), and hepatomegaly (X²=6.423, p=0.01). Lipid profiles and gender differences were not significant between groups. Conclusions: This study demonstrates, for the first time, that both genetic and phenotypic markers distinguish TD patients with cardiovascular complications. Future research is needed to confirm whether these differences reflect distinct disease mechanisms.