Genetic basis of hypercholesterolemia in adults

Abstract We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minne...

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Autores principales:	Seyedmohammad Saadatagah, Merin Jose, Ozan Dikilitas, Lubna Alhabi, Alexandra A. Miller, Xiao Fan, Janet E. Olson, David C. Kochan, Maya Safarova, Iftikhar J. Kullo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/5c962de15c504427a84a1f17c57c7dba
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spelling	oai:doaj.org-article:5c962de15c504427a84a1f17c57c7dba2021-12-02T14:27:46ZGenetic basis of hypercholesterolemia in adults10.1038/s41525-021-00190-z2056-7944https://doaj.org/article/5c962de15c504427a84a1f17c57c7dba2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00190-zhttps://doaj.org/toc/2056-7944Abstract We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.Seyedmohammad SaadatagahMerin JoseOzan DikilitasLubna AlhabiAlexandra A. MillerXiao FanJanet E. OlsonDavid C. KochanMaya SafarovaIftikhar J. KulloNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Seyedmohammad Saadatagah Merin Jose Ozan Dikilitas Lubna Alhabi Alexandra A. Miller Xiao Fan Janet E. Olson David C. Kochan Maya Safarova Iftikhar J. Kullo Genetic basis of hypercholesterolemia in adults
description	Abstract We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.
format	article
author	Seyedmohammad Saadatagah Merin Jose Ozan Dikilitas Lubna Alhabi Alexandra A. Miller Xiao Fan Janet E. Olson David C. Kochan Maya Safarova Iftikhar J. Kullo
author_facet	Seyedmohammad Saadatagah Merin Jose Ozan Dikilitas Lubna Alhabi Alexandra A. Miller Xiao Fan Janet E. Olson David C. Kochan Maya Safarova Iftikhar J. Kullo
author_sort	Seyedmohammad Saadatagah
title	Genetic basis of hypercholesterolemia in adults
title_short	Genetic basis of hypercholesterolemia in adults
title_full	Genetic basis of hypercholesterolemia in adults
title_fullStr	Genetic basis of hypercholesterolemia in adults
title_full_unstemmed	Genetic basis of hypercholesterolemia in adults
title_sort	genetic basis of hypercholesterolemia in adults
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5c962de15c504427a84a1f17c57c7dba
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Genetic basis of hypercholesterolemia in adults

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