Genetics of LDL Cholesterol 

Low-density lipoprotein cholesterol (LDLc) is a primary mediator of the development of atherosclerotic vascular disease. Although there is wide inter-individual variability in levels of LDLc, several studies have demonstrated that LDLc levels in related individuals tend to be similar, indicating that LDLc levels are a heritable trait.^[1] Because of these observations, there has been considerable investigation into the genetic determinants of LDLc so as to predict risk of future cardiovascular disease as well as to identify novel targets for pharmacologic inhibition.

Broadly speaking, the genetics of LDLc can be grouped by their pattern of inheritance within families. Some individuals with elevated LDLc, for example, have a single variant in a single gene that affects the LDLc. The pattern of inheritance for these single variants can easily be classified as autosomal dominant or recessive (ie, Mendelian inheritance). This class of single variants represents, in general, rare variants that individually lead to large changes in LDLc. By contrast, the genetic determinants in other individuals with elevated LDLc are not easily described by a single variant and do not show a clear pattern of inheritance. This second class of variants represents, in general, more common variants that each exerts small effects on LDLc, and suggest a more complex interaction between multiple genetic variants that act in concert with each other (and with dietary factors) to affect levels of LDLc.

To see complete information on the role of LDLc in atherosclerosis, please go to the main article by clicking here.

Single variants that dramatically elevate LDLc levels (ie, LDLc > 200-400 mg/dL) are found in the following genes: LDLR, APOB, ARH, ABCG5, ABCG8, and PCSK9. In addition, single variants that markedly reduce (ie, LDLc < 60 mg/dL) are found in MTP, APOB, and PCSK9. These single variants are rare, found in fewer than 1 in 500 individuals. Nevertheless, because they exert such a profound effect on LDLc levels, carriers of these mutations have dramatically altered risks of coronary heart disease (CHD). For example, carriers of two mutations in LDLR (a condition known as familial hypercholesterolemia) results in marked elevation of LDLc > 500 mg/dL, tendon xanthomas, and CHD that develops in the third and fourth decades of life. Similarly, variants in PSCK9 that lead to reductions in LDLc to < 100 mg/dL are associated with a reduced incidence of CHD.^[2]

Many mutations in each of these genes have been identified; often, a rare variant identified in one family may not be found in other families with elevated LDLc. As discussed below, this has implications regarding genetic testing for diagnosis.

The second class of variants that affect LDLc include those in the following genes (reference sequence identifier in parentheses): APOB (rs693), APOE (rs4420638), HMGCR (rs12654264), LDLR (rs688), PCSK9 (rs11591147), and SORT1 (rs12740374). In total, more than 30 genetic variants have now been associated with LDLc.

In general, these variants are more common, found in more than 1 in 100 individuals, but are responsible for smaller changes in LDLc, typically 10 mg/dL per mutation. It has been proposed that, because they are common, an individual might carry multiple variants across many genes that all work in concert to effect LDLc levels.^[3] Consequently, investigators have created “genotype scores” that are calculated by summing the number of LDLc-related variants found in an individual. This score, which is a reflection of the genetic burden carried by the individual, has been shown to predict LDLc levels and the subsequent risk of CHD.^[4]

That being said, associations between LDLc with single variants or the genotype score with CHD, although interesting, are unlikely to improve risk prediction beyond established cardiovascular risk factors or even beyond simply measuring LDLc. Their importance, though, is two-fold: first, they highlight the critical causative role that LDLc plays in the pathogenesis of CHD; second, they imply that life-long reductions in LDLc lead to reduced CHD risk with no other apparent adverse consequences. The implications of this work may lead to measuring LDLc at younger ages and lowering the thresholds to treat LDLc. At this time, however, using genetic testing to guide preventative therapies is not recommended.

Because the single variant disorders are, in general, caused by rare variants, few companies offer genetic testing. In addition, individuals may carry novel mutations that have not yet been identified in other families. On the other hand, because many of these disorders are diagnosed based on clinical criteria alone, genetic testing is often not necessary. If knowledge of the specific genetic variant is required, sequencing of the entire or certain portions of the gene can be performed.

Despite these limitations, because there are effective therapeutics that can lower LDLc in patients with familial hypercholesterolemia, there is a potential benefit to genetic testing as early treatment might delay the development of CHD and ultimately prove cost effective. Therefore, some have advocated genetic testing in family members of those diagnosed with the disease.^[5]

Although the concept of genotyping the more common variants is appealing, at this time, there are no commercially available tests.