PCSK9 in African Americans and Caucasians in Relation to Lp(a) Level, Apo(a) Size and Heritability

Enkhmaa, Byambaa; Kim, Kyoungmi; Zhang, Wei; Prakash, Nishant; Truax, Kevin; Anuurad, Erdembileg; Berglund, Lars

doi:10.1210/jendso/bvaa073

Cited by 8 publications

(2 citation statements)

References 32 publications

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“…So far, no GWAS of PCSK9 levels in African Americans has been published. Although a recently conducted study estimated the PCSK9 heritability at 47% in Europeans ( 11 ), SNPs described so far only explained 4% of the trait’s variance ( 9 ). This and the limited sample size of previous studies ( N = 1215 and N = 3290) suggest that further genetic associations could be discovered.…”

Section: Introductionmentioning

confidence: 99%

Meta-GWAS of PCSK9 levels detects two novel loci atAPOBandTM6SF2

Pott

Gådin

Theusch

et al. 2021

Human Molecular Genetics

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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades LDL receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by LDL-C. Methods & Results We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12,721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. Conclusion Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. While the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.

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Section: Introductionmentioning

confidence: 99%

Meta-GWAS of PCSK9 levels detects two novel loci atAPOBandTM6SF2

Pott

Gådin

Theusch

et al. 2021

Human Molecular Genetics

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“…Our study showed a strong positive association between PCSK9 concentrations and future CV events in Asian patients. The frequency of PCSK9 variations and concentrations vary among different ethnic groups ( 44 , 45 ). The PCSK9 R46L and A443T variants are associated with lower LDL-C concentrations.…”

Section: Discussionmentioning

confidence: 99%

Association Between Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations and Cardiovascular Events in Cardiovascular Disease: A Systemic Review and Meta-Analysis

Liu

Fan

Luo

et al. 2021

Front. Cardiovasc. Med.

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Background: A large amount of evidence suggests that proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors have clinical benefits in patients with cardiovascular disease (CVD). However, whether PCSK9 concentrations predict future cardiovascular (CV) events remains unclear.Methods: We conducted a meta-analysis to investigate the ability of PCSK9 concentrations to predict future CV events in patients with established CVD. A comprehensive search of electronic databases was conducted in June 2021. We included relative risk (RR) estimates with 95% CI or events of interest.Results: Eleven cohort studies including 8,471 patients with CVD were enrolled. The pooled RR of CV events for the increase in the circulating baseline PCSK9 concentrations by 1 SD showed a positive association in a random-effect model (RR 1.226, 95% CI: 1.055–1.423, P = 0.008). Similarly, the risk of the total CV events increased by 52% in the patients in the highest tertile compared with those in the lowest tertile of circulating PCSK9 concentrations (RR 1.523, 95% CI: 1.098–2.112, P = 0.012). The association between PCSK9 and CV events was stronger in stable patients with CVD, patients treated with statins, and Asian patients.Conclusions: High PCSK9 concentrations are significantly related to the increased risk of future CV events. These results enrich the knowledge of PCSK9 function and suggest the further possible clinical role of PCSK9 inhibitors.

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