Author: Endonita Hajzeraj
What is likely the first question that is asked when you visit a doctor about a concern you may have? The question that is always asked is, does anyone in your family have or has had this disease. Yes, genetics is important when it comes to your health. It can be a contributing factor for many diseases, including coronary artery disease. Although CAD is highly preventable, sometimes it just runs in your family, which puts you at a higher risk for developing that disease. Genetic factors contribute to the risk of CAD, and in the past decade, there has been major progress in the area. Genome-wide association studies encompassing masses of people, bioinformatics approaches, 1000 genomes imputation expression, and interrogation of encyclopedia of DNA elements has allowed for the emergence of more than 60 common SNPs to be associated with CAD risk (1). It has been estimated the heritability of CAD has been 40-60% primarily based on family studies.
Genetic variants and mutations can occur that disable or enable certain proteins in the CAD process. Several sequence variants have been known to have effects on serum of non-HDL cholesterol that alter the risk of coronary artery disease (2). In a study conducted by Nioi et al. they sequenced the genome of nearly 3000 Icelanders and found variants that they then imputed into the genomes of nearly 400k Icelanders. They tested for the association between the imputed variants and non-HDL cholesterol levels (2). The researchers found a rare non-coding 12-base pair deletion in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins (2). The mutation activates a splice site, leading to a frameshift mutation an a premature stop codon that makes the protein prone to degradation. Heterozygous carriers of the mutation, has a lower level of non-HDL protein, thus a lower risk for CAD (2). With this study, they concluded that a single copy of the functional ASGR1 was associated with reduced levels of non-HDL and, thus, CAD.
Impact of genetics on our lifestyle is always prominent. For some, eating healthy is all they do, and yet they still may have hypercholesterolemia. Familial hypercholesterolemia plays a role in the prevalence of coronary artery disease. Tada and colleagues conducted a study on the impact of positive clinical signs, such as family history, and positive family hypercholesterolemia (FH) mutation status on the risk of CAD (3). There are three causative agents for familial hypercholesterolemia. LDLR, APOB, and PCSK9 were sequenced in nearly 700 patients with severe hypercholesterolemia and the presence of FH signs were assessed. CAD prevalence was compared between subject groups categorized based on FH mutations or clinical signs of FH, those with clinical signs of FH or FH mutations has three to four fold higher odds of developing CAD (3). Their findings conclude that FH mutations had positive effects to CAD risk among patients with significantly elevated LDL cholesterol. This helps us determine and continue to push the field forward in determining risk factors, like familial hypercholesterolemia, for CAD.
- McPherson, Ruth, and Anne Tybjaerg-Hansen. 2016. “Genetics of Coronary Artery Disease.” Circulation Research 118 (4): 564–78. https://doi.org/10.1161/CIRCRESAHA.115.306566.
- Nioi, Paul, Asgeir Sigurdsson, Gudmar Thorleifsson, Hannes Helgason, Arna B. Agustsdottir, Gudmundur L. Norddahl, Anna Helgadottir, et al. 2016. “Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.” New England Journal of Medicine 374 (22): 2131–41. https://doi.org/10.1056/NEJMoa1508419.
- Tada, Hayato, Masa-aki Kawashiri, Atsushi Nohara, Akihiro Inazu, Hiroshi Mabuchi, and Masakazu Yamagishi. 2017. “Impact of Clinical Signs and Genetic Diagnosis of Familial Hypercholesterolaemia on the Prevalence of Coronary Artery Disease in Patients with Severe Hypercholesterolaemia.” European Heart Journal 38 (20): 1573–79. https://doi.org/10.1093/eurheartj/ehx004.
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