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Published on: August 28, 2018
New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol
Fan-Hua Meng1,2,3,4, Shuai Liu1,2,3, Jian Xiao3
1Heart Center (F.-H.M., S.L., Y.-T.M., Z.-Y.F.), First Affiliated Hospital of Xinjiang Medical University, China.
Background:
Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported.
Methods:
The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet.
Results:
We identified 2 PCSK9 mutations-E144K and C378W-in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus-mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum.
Conclusions:
Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.
Insights
Two novel PCSK9 mutations, E144K and C378W, were identified in Chinese Uyghurs, leading to lower LDL cholesterol levels. These loss-of-function mutations impair PCSK9 protein function, reducing cardiovascular disease risk.
Area of Science:
- Genetics
- Biochemistry
- Cardiovascular Disease Research
Background:
- Lowering low-density lipoprotein cholesterol (LDL-C) reduces atherosclerotic cardiovascular disease risk.
- PCSK9 loss-of-function mutations are linked to low LDL-C in various populations.
- PCSK9 genetic variants in Chinese Uyghurs, a high-risk group, remain largely uncharacterized.
Purpose of the Study:
- To investigate PCSK9 genetic variants associated with low LDL-C in Chinese Uyghurs.
- To elucidate the functional impact of identified PCSK9 mutations on LDL-C regulation.
- To validate the causal role of these mutations in vivo.
Main Methods:
- Whole-exome and targeted sequencing of Uyghur and other ethnic groups in Xinjiang.
- In vitro biochemical and cell assays to assess PCSK9 protein function.
- In vivo studies using adeno-associated virus-mediated gene transfer in PCSK9 knockout mice fed a high-cholesterol diet.
Main Results:
- Identified two PCSK9 mutations, E144K and C378W, in Chinese Uyghurs with low LDL-C.
- E144K and C378W mutations impaired PCSK9 maturation and secretion, respectively.
- In vivo studies confirmed reduced PCSK9 secretion, increased LDL receptor levels, and lower LDL-C in mice expressing these mutants.
Conclusions:
- E144K and C378W represent novel PCSK9 loss-of-function mutations.
- These mutations contribute to lower LDL-C levels, likely through impaired PCSK9 function.
- Findings suggest a potential role for these mutations in modulating cardiovascular risk in humans.
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