11 Jul, 16 | by flee
The links between cholesterol and coronary artery disease are well established and incontrovertible, with modification of serum LDL cholesterol levels repeatedly shown to reduce risk of myocardial infarction and cardiovascular death. But total non-HDL cholesterol levels, encompassing multiple other lipid fractions including Lp(a) and chylomicrons, have the strongest overall association with the risk of incipient coronary artery disease. In this large genome-wide association study, the authors identify a novel noncoding 12-base-pair deletion in intron 4 of the ASGR1 gene that appears to be associated with lower levels of non-HDL cholesterol. In an initial discovery cohort of 2636 Icelanders, the polymorphism was associated with a reduced risk of atherosclerotic coronary disease. Further testing in a cohort of 398,000 Icelanders demonstrated a prevalence of heterozygous carriers of approximately 1 in 120. These carriers had lower levels of non-HDL cholesterol and a significant 34% reduction in rates of coronary artery disease (95% CI, 21 to 45; P=4.0×10(-6)). To further validate these associations, five other large European cohorts containing a total of 42,524 case patients and 249,414 controls were analyzed with results consistent to those seen in the Icelandic cohort. Finally, the authors describe a second loss of function polymorphism in the same ASGR1 gene that again leads to significantly reduced levels of non-HDL cholesterol in carriers, validating their initial hypothesis that ASGR1 is directly implicated in non-HDL cholesterol homeostasis.