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.

Conclusions

In this large genetic study, polymorphisms in the gene ASGR1, which encodes part of a receptor that regulates levels of circulating glycoproteins, are strongly implicated in determining levels of non-HDL cholesterol and associated with corresponding reductions in the risk of coronary artery disease.  While further work to understand the mechanisms of ASGR1 are required, the delineation of a previously undescribed association may create opportunities for future pharmacological manipulation of ASGR1 with implications for coronary disease prevention.

Nioi P, Sigurdsson A, Thorleifsson G, Helgason H, Agustsdottir AB, Norddahl GL, Helgadottir A, Magnusdottir A, Jonasdottir A, Gretarsdottir S, Jonsdottir I, Steinthorsdottir V, Rafnar T, Swinkels DW, Galesloot TE, Grarup N, Jørgensen T, Vestergaard H, Hansen T, Lauritzen T, Linneberg A, Friedrich N, Krarup NT, Fenger M, Abildgaard U, Hansen PR, Galløe AM, Braund PS, Nelson CP, Hall AS, Williams MJ, van Rij AM, Jones GT, Patel RS, Levey AI, Hayek S, Shah SH, Reilly M, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Kiemeney LA1, Quyyumi AA, Rader DJ, Kraus WE, Samani NJ, Pedersen O, Thorgeirsson G, Masson G, Holm H, Gudbjartsson D, Sulem P, Thorsteinsdottir U, Stefansson K. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.  N Engl J Med. 2016 Jun 2;374(22):2131-41.

Authors: Hussain Contractor, James M. McCabe