Abstract
Familial hypercholesterolemia (FH) is caused by mutations in LDLR (low-density lipoprotein receptor), APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), or APOE (apolipoprotein E) genes in approximately 80% of the cases. Polygenic forms of hypercholesterolemia may be present among patients clinically diagnosed with FH but with no identified mutation (FH mutation-negative (FH/M−)). To address whether polygenic forms may explain phenocopies in FH families, we calculated a 6-single-nucleotide polymorphism (SNP) genetic risk score (GRS) in all members from five French FH families where a mutation was identified (FH/M+) as well as some phenocopies (FH/M−). In two families, three FH/M− patients present a high GRS suggesting a polygenic hypercholesterolemia for these phenocopies. However, a high GRS is also observed in nine FH/M+ patients and in four unaffected relatives from three families. These observations indicate that the GRS does not seem to be a good diagnostic tool at the individual level. Nevertheless, the GRS seems to be a contributor of the severity of hypercholesterolemia since patients who cumulate a mutation and a high GRS exhibit higher low-density lipoprotein cholesterol levels when compared to patients with only FH (p = 0.054) or only polygenic hypercholesterolemia (p = 0.0039). In conclusion, the GRS can be used as a marker of the severity of hypercholesterolemia but does not seem to be a reliable tool to distinguish phenocopies within FH families.
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Acknowledgements
We thank all patients and their relatives for their participation in this study. We would like to thank Dr. Marta Futema and Pr. Steve Humphries for constructive discussions and for providing us some of their data. This work was supported by a grant from Leducq Foundation (FLQ # 13 CVD 03) through the Transatlantic Networks of Excellence in Cardiovascular Research program (“The function and regulation of PCSK9: a novel modulator of LDLR activity”); and Institut National de la Santé et de la Recherche Médicale (INSERM); and Conseil de la Recherche de l’Université Saint-Joseph, Beirut, Lebanon; and Lebanese National Council for Scientific Research (CNRS-L). This work was also supported by the national project CHOPIN (CHolesterol Personalized Innovation) granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007) and coordinated by the Centre Hospitalo-Universitaire (CHU) de Nantes. YG and SE are supported by grants from Lebanese National Council for Scientific Research (CNRS-L); and Council of Research of Saint-Joseph University of Beirut, Lebanon and Institut Français du Liban.
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Ghaleb, Y., Elbitar, S., El Khoury, P. et al. Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?. Eur J Hum Genet 26, 570–578 (2018). https://doi.org/10.1038/s41431-017-0078-y
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DOI: https://doi.org/10.1038/s41431-017-0078-y
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