Elsevier

Atherosclerosis

Volume 193, Issue 2, August 2007, Pages 445-448
Atherosclerosis

The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population

https://doi.org/10.1016/j.atherosclerosis.2006.08.039Get rights and content

Abstract

Objective

Missense mutations in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) can cause familial hypercholesterolemia. However, two nonsense variants of PCSK9, Y142X and C679X, found in ∼2% of black American subjects, are associated with a 28% reduction in mean low density lipoprotein (LDL)–cholesterol. We sought to determine the frequency and effect of these nonsense variants in an African population.

Methods and results

PCSK9 genotypes were determined in 653 black African women attending two antenatal clinics in Zimbabwe. C679X occurred in 3.7% of subjects and was associated with a 27% reduction in LDL–cholesterol (1.6 ± 0.3 mmol/L versus 2.2 ± 0.7 mmol/L in non-carriers). We did not observe the Y142X variant.

Conclusions

Our results show that the PCSK9 C679X variant has a marked cholesterol-lowering effect.

Section snippets

Subjects

Fasting blood samples were obtained from 653 young black females attending postnatal clinics at the Mabvuku Polyclinic and Edith Opperman Maternity Hospital in Zimbabwe. Approval was obtained for these studies from the University of Cape Town Ethics Committee and the Medical Research Council of Zimbabwe and all participants signed written consent.

Analyses

After venesection, blood was promptly processed before freezing plasma and white blood cells for later analysis in batches. Plasma cholesterol and

Results

Genotyping of the two PCSK9 nonsense mutations in the 653 samples revealed that C679X occurred in 3.7% of subjects (n = 24), which included one homozygote (Table 1). This gives an allele frequency of 0.019. None of the 653 subjects carried the Y142X variant. The C679X variant was associated with a 27 percent reduction in LDL–cholesterol and did not influence plasma HDL–cholesterol or triglyceride concentrations. Of interest, the C679X homozygous subject had the lowest LDL–cholesterol out of the

Discussion

Our findings show that the PCSK9 nonsense variant C679X occurs in 3.7% of Zimbabwean blacks and is associated with a 27% reduction in LDL–cholesterol (1.6 ± 0.3 mmol/L versus 2.2 ± 0.7 mmol/L in non-carriers). These results are very similar to those of Cohen et al., who found PCSK9 nonsense mutations occurring in 2.6% of African Americans that were associated with a 28% reduction in LDL–cholesterol [11]. In addition to confirming that this commonly encountered mutation in the PCSK9 gene has a

Acknowledgments

Thanks to Dr. George Mantiri and Ms. Joanna Brisbane for assisting with DNA extractions. This work was supported by grants from the Raine Medical Research Foundation, National Health & Medical Research Council (403908), and National Heart Foundation of Australia (G 139 1155). Thanks to the Lotterywest State Biomedical Genomics Facility, Clinical Department of Immunology and Biochemical Genetics, Royal Perth Hospital, for the use of the ABI 7900HT. Partial support was also obtained from the

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