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PCSK9

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PCSK9

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The PCSK9 gene encodes a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9). It plays an extremely important role in ensuring that the levels of low-density lipoprotein (LDL), also known as the ‘bad cholesterol’, remain at healthy levels in the bloodstream.

LDL receptors bind to and remove LDL from the bloodstream, and when circulating LDL levels are at the correct concentration, PCSK9 then binds to, and degrades, these LDL receptors. Research has found that there are both “gain of function” and “loss of function” PCSK9 gene variations that occur.

The “gain of function” variants cause a significant increase in the activity of the PCSK9 protein. The result is that very few LDL receptors are available to remove LDL from the bloodstream.

The ‘loss-of-function” variants, on the other hand, mean that the PCSK9 protein has a very low level of activity, meaning that the LDL receptors can effectively remove LDL from the bloodstream.

The impact of PCSK9 gene variations

To date, a large body of evidence has shown that these variations contribute to a wide variation in individual blood cholesterol levels, even in those without a documented cholesterol disorder.

Familial hypercholesterolemia (elevated cholesterol levels) occurs when an individual has a “gain-of-function” variant in the PCSK9 gene. These individuals are at risk of developing cardiovascular diseases and cerebral strokes in some cases.

Individuals with ‘loss of function” variants present with life-long low total cholesterol and LDL levels and have a notably reduced incidence of coronary artery disease risk.

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

PCSK9 screening blood test

The effects of PCSK9 variants on cholesterol are so significant, that screening tests for the presence of the ‘gain of function mutations have been developed. This test is also known as:

  • Familial Early-Onset Coronary Heart Disease PCSK9 Blood Test
  • Familial Hypercholesterolemia Blood Test
  • FH PCSK9 Blood Test

This test is also used to evaluate the risk of familial cardiovascular disease. Drugs are also currently being developed that inhibit the PCSK9 protein, allowing the LDL receptors to remove the bad cholesterol from the circulation.

There are several SNPs associated with altered PCSK9 activity 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.

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