Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family

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Nikkola , E , Ko , A , Alvarez , M , Cantor , R M , Garske , K , Kim , E , Gee , S , Rodriguez , A , Muxel , R , Matikainen , N , Soderlund , S , Motazacker , M M , Boren , J , Lamina , C , Kronenberg , F , Schneider , W J , Palotie , A , Laakso , M , Taskinen , M-R & Pajukanta , P 2017 , ' Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family ' , Atherosclerosis , vol. 264 , pp. 58-66 . https://doi.org/10.1016/j.atherosclerosis.2017.07.024

Title: Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family
Author: Nikkola, Elina; Ko, Arthur; Alvarez, Marcus; Cantor, Rita M.; Garske, Kristina; Kim, Elliot; Gee, Stephanie; Rodriguez, Alejandra; Muxel, Reinhard; Matikainen, Niina; Soderlund, Sanni; Motazacker, Mahdi M.; Boren, Jan; Lamina, Claudia; Kronenberg, Florian; Schneider, Wolfgang J.; Palotie, Aarno; Laakso, Markku; Taskinen, Marja-Riitta; Pajukanta, Paivi
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Marja-Riitta Taskinen Research Group
Date: 2017-09
Language: eng
Number of pages: 9
Belongs to series: Atherosclerosis
ISSN: 0021-9150
URI: http://hdl.handle.net/10138/297951
Abstract: Background and aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). Methods: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). Results: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. Conclusions: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs. (c) 2017 Elsevier B.V. All rights reserved.
Subject: Familial hypercholesterolemia (FH)
LDL cholesterol
Genetic risk score (GRS)
Lipoprotein (a)
ATHEROSCLEROSIS SOCIETY
LIPOPROTEIN(A)
POPULATION
PHENOTYPES
MUTATIONS
DISEASE
MANAGEMENT
DIAGNOSIS
GENETICS
MODERATE
3121 General medicine, internal medicine and other clinical medicine
1184 Genetics, developmental biology, physiology
3111 Biomedicine
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