Elina Nikkola1, Arthur Ko2, Marcus Alvarez1, Rita M Cantor1, Kristina Garske1, Elliot Kim1, Stephanie Gee1, Alejandra Rodriguez1, Reinhard Muxel3, Niina Matikainen4, Sanni Söderlund5, Mahdi M Motazacker6, Jan Borén7, Claudia Lamina8, Florian Kronenberg8, Wolfgang J Schneider9, Aarno Palotie10, Markku Laakso11, Marja-Riitta Taskinen5, Päivi Pajukanta12. 1. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA. 2. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Molecular Biology Institute at UCLA, Los Angeles, USA. 3. General Practice Centre, Austria. 4. Endocrinology, Abdominal Centre, Helsinki University Hospital, Finland; Heart and Lung Center, Helsinki University Hospital, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Finland. 5. Heart and Lung Center, Helsinki University Hospital, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Finland. 6. Department of Clinical Genetics, Academic Medical Center at the University of Amsterdam, The Netherlands. 7. Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Sweden. 8. Division of Genetic Epidemiology, Medical University of Innsbruck, Austria. 9. Department Medical Biochemistry, Medical University Vienna and Max F. Perutz Laboratories, Austria. 10. Institute for Molecular Medicine, University of Helsinki, Finland; The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MA, USA. 11. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 12. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Molecular Biology Institute at UCLA, Los Angeles, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA. Electronic address: ppajukanta@mednet.ucla.edu.
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.
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.
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