Novel ABCA1 mutations in Tangier disease associated with early‐onset type 2 diabetes: A case report

Tangier disease (TD) is a rare disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene with autosomal recessive inheritance and is characterized by extremely low high-density lipoprotein cholesterol (HDL-C) and premature atherosclerosis. Although experimental studies suggest that ABCA1 plays an important role in pancreatic β-cell cholesterol homeostasis, its clinical contribution to diabetes development in humans remains unclear. We report a 69-year-old Japanese man with early-onset type 2 diabetes mellitus, profound hypo-HDL cholesterolemia (HDL-C 5 mg/dL), and severe atherosclerotic cardiovascular disease. Genetic analysis identified compound heterozygous ABCA1 variants (p.Arg104Cys and the novel p.Asp1706Tyr), both of which were predicted to be potentially pathogenic, although direct functional validation was not performed. Despite a 40-year duration of diabetes, endogenous insulin secretion was partially preserved. This case highlights phenotypic variability in TD and suggests that variant-specific effects on ABCA1 function and polygenic susceptibility may influence diabetes development in humans.