PCSK9

Protein:

PCSK9

Not sure what to eat?

Get a custom nutrition plan.

Start Here

The PCSK9 gene encodes a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9). This protein grabs onto receptors for low density lipoprotein after they transport cholesterol into cells. By doing so, the PCSK9 protein facilitates the breakdown of the LDL receptors, meaning fewer make it back to the cell surface. See also: Should I take a PCSK9 inhibitor?

When a person has a variant of the PCSK9 gene that leads to high levels of PCSK9 protein, they have fewer LDL receptors to clear LDL cholesterol from the bloodstream. These mutations are “gain-of-function” variants, because they increase the activity of the PCSK9 protein. Such variations are associated with a condition called familial hypercholesterolemia (FH). FH is characterized by an increase in cholesterol levels. This condition  also increases the risk for cardiovascular disease and events.

PCSK9 has also been referred to as:

  • FH3
  • HCHOLA3
  • hypercholesterolemia, autosomal dominant 3
  • NARC-1
  • NARC1
  • neural apoptosis regulated convertase 1
  • PCSK9_HUMAN
  • Proprotein convertase PC9
  • Subtilisin/kexin-like protease PC9.

The PCSK9 gene is located on chromosome 1 at position 32.3 (on the short arm). The cytogenic location is 1p32.3.

The impact of PCSK9 mutations

Researchers have identified more than 50 PCSK9 gene mutations associated with FH. These mostly cause a change in single amino acids in the protein. Most people with FH inherit one normal (wild type) copy of the PCSK9 gene and one altered copy. The effects of the altered gene typically appear in a person’s late forties or fifties.

Those rare individuals who inherit two mutated “gain-of-function” copies will have more severe FH, with effects first appearing in childhood.

In some cases, mutations in the gene lead to a loss of function. Loss of function means lower cholesterol levels. Why? Because when there is little or no PCSK9 protein, LDL receptors can continue to clear cholesterol from the blood. Loss-of-function PCSK9 mutations appear to be more common than those causing FH, although are still not common in the general population. These mutations can significantly reduce a person’s risk of developing cardiovascular disease.

Researchers now think that PCSK9 variations (polymorphisms) likely contribute to the wide variation in individual blood cholesterol levels, even in those without a documented cholesterol disorder.

In addition, newer research is investigating the potential link between altered PCSK9 activity and Alzheimer’s disease. 1,2

There are several SNPs associated with altered PCSKactivity which are detailed below.

E670G

Science Grade
A-
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs505151 a g 10GlyGln

Risk Description

The risk ‘G’ allele of PCSK9 rs505151 (c.2009G > A, E670G) was associated with increased triglyceride (TG) and LDL-C levels, as well as increased cardiovascular risk. 3 Risk allele carriers of E670G have also been seen to get no significant benefit from statin treatment compared to homozygous wild type carriers who do benefit. 4,5

Lifestyle Considerations:

BehaviorDescription
Response to statin treatment

Carriers of the risk allele “G” have been shown to respond less well to statin treatment compared to those carrying non-risk alleles. Therefore, individuals may wish to discuss this with their healthcare provider, and identify alternative cholesterol reduction therapies.

Discuss this information with your doctor before taking any course of action.

V474I

Science Grade
B+
Heart Health

R46L

Science Grade
A-
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs11591147 g t 1ArgHis

Risk Description

The rs11591147 polymorphism is a loss-of-function mutation, 7 meaning that the non-risk allele (rs11591147) is associated with lower LDL-cholesterol and a lower risk of coronary heart disease. 8 However, the frequency of this polymorphism is low and so most people will carry the risk “G” major allele.

Specifically, the variant T allele of rs11591147 (c.137G > T, R46L) appears to protect carriers against cardiovascular disease and lowers TC and LDL-C levels in Caucasians. 9 In one other study (a large prospective cohort study), rs11591147 carriers were seen to have both lower levels of lipoprotein(a) and LDL cholesterol and a reduced risk of aortic valve stenosis and myocardial infarction.

Discuss this information with your doctor before taking any course of action.

L253F

Science Grade
A-
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs72646508 c t 0.19LeuPhe

Risk Description

rs72646508 is another loss of function polymorphism in the PCKS9 gene. The minor allele “T” is associated with reduced LDL-C and significantly lowered risk for coronary events. As with other PCKS9 SNPs the frequency of the non-risk allele is low in the population. 11,12

Discuss this information with your doctor before taking any course of action.

G1327A

Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs28362263 g a 7AlaPro

Risk Description

rs28362263 is a loss of function polymorphism in the PCKS9 gene. The minor allele “A” is associated with reduced LDL-C (approximately 3% reduction) and a moderately lowered risk for coronary events. As with other PCKS9 SNPs the frequency of the non-risk allele is low in the population. 13,14

Discuss this information with your doctor before taking any course of action.

C2037A

Science Grade
B-
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid
rs28362286 c a 0.5Cys

Risk Description

rs28362286 is a loss of function polymorphism in the PCKS9 gene, where the minor “A” allele has a significant impact on LDL-C, with reductions upwards of 40% reported. This reduction in LDL-C is also associated with a very significant reduction in coronary event risk. 15

Discuss this information with your doctor before taking any course of action.

Facebook icon Twitter icon Instagram icon Pinterest icon Google+ icon YouTube icon LinkedIn icon Contact icon Info icon