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Effect of Loss-of-Function Genetic Variants in PCSK9 on Glycemic Traits, Neurocognitive Impairment, and Hepatobiliary Function

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posted on 10.11.2021, 22:04 by Jonas Ghouse, Gustav Ahlberg, Henning Bundgaard, Morten S. Olesen
OBJECTIVE: To evaluate the association between PCSK9 predicted loss-of-function variants (pLoF) and glycemic traits, hepatobiliary function and neurocognitive traits.

RESEARCH DESIGN AND METHODS: We identified carriers of PCSK9 pLoF in UK Biobank exome sequencing data. We assessed the aggregate effects of these variants on lipid/lipoprotein traits, which served as a positive control. Association of PCSK9 pLoF carrier status and glycemic traits, hepatobiliary function, neurocognitive traits was then evaluated as a measure for adverse effects.

RESULTS: We identified 374 individuals with 41 pLoF variants. As expected, we found that PCSK9 pLoF carriers had significantly lower LDL-C (P = 7.4 × 10-55) and apoB levels (P = 7.6 × 10-50) compared with noncarriers. However, we found no significant associations between pLoF carrier-status and glycemic traits, hepatobiliary function and neurocognitive traits (P > 0.05).

CONCLUSIONS: Our results do not support adverse effects of PCSK9 pLoF on glycemic traits, hepatobiliary function or neurocognitive traits.


This work was funded by BRIDGE - Translational Excellence Programme (#NNF18SA0034956 and #NNF20SA0064340), The John and Birthe Meyer Foundation, The Innovation Fund Denmark (PM Heart), NordForsk, The Hallas-Møller Emerging Investigator.