ABSTRACT
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).
Subject(s)
Cholesterol, HDL/blood , Coronary Disease/blood , Coronary Disease/genetics , Scavenger Receptors, Class B/genetics , Aged , Amino Acid Substitution , Animals , DNA Mutational Analysis , Female , Genetic Variation , Heterozygote , Homozygote , Humans , Leucine/genetics , Male , Mice , Middle Aged , Proline/genetics , Protein Processing, Post-Translational , Risk , Scavenger Receptors, Class B/metabolismABSTRACT
BACKGROUND: South Asians have a higher overall incidence rate and younger age of onset for acute myocardial infarction (AMI) compared to Western populations. However, limited information is available on the association of preventable risk factors and outcomes of AMI among young individuals in Bangladesh. The aim of this study was to determine the risk factors and in-hospital outcome of AMI among young (age ≤40 years) adults in Bangladesh. METHODS: We conducted a prospective observational study among consecutive 50 patients aged ≤40 years and 50 patients aged >40 years with acute ST Segment Elevation Myocardial Infarction (STEMI) and followed-up in-hospital at the National Institute of Cardiovascular Diseases (NICVD). Clinical characteristics, biochemical findings, diet, echocardiography and in-hospital outcomes were compared between the two groups. Multivariate logistic regression was performed to assess the association between risk factors and in-hospital outcome in young patients adjusting for other confounding variables. RESULTS: The mean age of the young and older patient groups was 36.5 ± 4.6 years and 57.0 ± 9.1 years respectively. Male sex (OR 3.4, 95 % CI 1.2 - 9.75), smoking (OR 2.4, 95 % CI 1.04 - 5,62), family history of MI (OR 2.4, 95 % CI 1.11 - 5,54), homocysteine (OR 1.2, 95 % CI 1.08 - 1.36), eating rice ≥2 times daily (OR 3.5, 95 % CI 1.15 - 10.6) and eating beef (OR 4.5, 95 % CI 1.83 - 11.3) were significantly associated with the risk of AMI in the young group compared to older group. In multivariate analysis, older patients had significantly greater chance of developing heart failure (OR 7.5, 95 % CI 1.51 to 37.31), re-infarction (OR 7.0, 95 % CI 1.08 - 45.72), arrhythmia (OR 15.3, 95 % CI 2.69 - 87.77) and cardiogenic shock (OR 69.0, 95 % CI 5.81 - 85.52) than the younger group. CONCLUSION: Younger AMI patients have a different risk profile and better in-hospital outcomes compared to the older patients. Control of preventable risk factors such as smoking, unhealthy diet, obesity and dyslipidemia should be reinforced at an early age in Bangladesh.
