Mark Trinder1, Maria L DeCastro2, Hawmid Azizi2, Luba Cermakova2, Linda M Jackson2, Jiri Frohlich2, G B John Mancini3, Gordon A Francis4, Liam R Brunham5. 1. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada. 2. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. 3. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 4. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 5. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: liam.brunham@ubc.ca.
Abstract
BACKGROUND: Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why. OBJECTIVES: This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically. METHODS: We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486). RESULTS: Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH. CONCLUSIONS: These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.
BACKGROUND:Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why. OBJECTIVES: This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically. METHODS: We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486). RESULTS:Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemicpatients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH. CONCLUSIONS: These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.
Authors: Rodrigo Alonso; Rosa Argüeso; Pilar Álvarez-Baños; Ovidio Muñiz-Grijalvo; Jose Luis Diaz-Diaz; Pedro Mata Journal: Curr Atheroscler Rep Date: 2022-04-07 Impact factor: 5.113
Authors: Martín Laclaustra; Fernando Civeira; Victoria Marco-Benedí; Ana M Bea; Ana Cenarro; Estíbaliz Jarauta Journal: Lipids Health Dis Date: 2022-08-02 Impact factor: 4.315