TY - JOUR
T1 - Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family
AU - Nikkola, Elina
AU - Ko, Arthur
AU - Alvarez, Marcus
AU - Cantor, Rita M.
AU - Garske, Kristina
AU - Kim, Elliot
AU - Gee, Stephanie
AU - Rodriguez, Alejandra
AU - Muxel, Reinhard
AU - Matikainen, Niina
AU - Söderlund, Sanni
AU - Motazacker, Mahdi M.
AU - Borén, Jan
AU - Lamina, Claudia
AU - Kronenberg, Florian
AU - Schneider, Wolfgang J.
AU - Palotie, Aarno
AU - Laakso, Markku
AU - Taskinen, Marja-Riitta
AU - Pajukanta, Päivi
PY - 2017
Y1 - 2017
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.atherosclerosis.2017.07.024
DO - https://doi.org/10.1016/j.atherosclerosis.2017.07.024
M3 - Article
C2 - 28772107
SN - 0021-9150
VL - 264
SP - 58
EP - 66
JO - Atherosclerosis
JF - Atherosclerosis
ER -