Risk Haplotype of BTNL2 Predisposes Male Patients to NSTEMI: A Genetic and Functional Study

Immunogenetic factors constitute major pathways contributing to the susceptibility to atherosclerosis and coronary artery disease. Through targeted whole-genome sequencing and replications in sex-specific cohorts with ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) we discovered a novel haplotype in the butyrophilin-like 2 (BTNL2) gene that predisposes men to NSTEMI. This risk haplotype is associated with the number and composition of extra-large high-density lipoproteins, and enhanced aggregation of low-density lipoproteins. Affected individuals have changes in BTNL2 expression. Furthermore, patients with risk haplotype and decreased BTNL2 serum concentration had improved survival. Our results identify BTNL2 as a compelling candidate gene in men with NSTEMI and suggest a previously unrecognized immuno-lipid regulatory mechanism contributing to disease susceptibility and outcome. The study highlights the importance of precise clinical characterisation and specific diagnoses in genetic studies of cardiovascular diseases.