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

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.

• Authors: Elina Nikkola, Arthur Ko, Marcus Alvarez, Rita M Cantor, Kristina Garske, Elliot Kim, Stephanie Gee, Alejandra Rodriguez, Reinhard Muxel, Niina Matikainen, Sanni Söderlund, Mahdi M Motazacker, Jan Borén, Claudia Lamina, Florian Kronenberg, Wolfgang J Schneider, Aarno Palotie, Markku Laakso, Marja-Riitta Taskinen, Päivi Pajukanta
• Journal: Atherosclerosis (Atherosclerosis) Vol. 264 Pg. 58-66 (Sep 2017) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 28772107 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• APOB protein, human
• Apolipoprotein B-100
• Biomarkers
• LDLR protein, human
• Lipoprotein(a)
• Receptors, LDL
• Cholesterol

Topics

• Apolipoprotein B-100 (genetics)
• Austria
• Biomarkers (blood)
• Cholesterol (blood)
• DNA Mutational Analysis
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Heredity
• Humans
• Hyperlipoproteinemia Type II (blood, diagnosis, genetics)
• Lipoprotein(a) (blood, genetics)
• Male
• Middle Aged
• Mutation
• Pedigree
• Phenotype
• Polymorphism, Single Nucleotide
• Receptors, LDL (genetics)
• Risk Factors
• Exome Sequencing