Lipoprotein(a) and family history for cardiovascular disease in paediatric patients: A new frontier in cardiovascular risk stratification. Data from the LIPIGEN paediatric group

Capra, Maria Elena; Fabrizi, Enrico; Catapano, Alberico L.; Bertolini, Stefano; Calandra, Sebastiano; Tarugi, Patrizia; Pellegatta, Fabio; Arca, Marcello; Averna, Maurizio; Bartuli, Andrea; Biasucci, Giacomo; Borghi, Claudio; Calabrò, Paolo; Carubbi, Francesca; Cipollone, Francesco; Citroni, Nadia; Maria, Del Ben; Fortunato, Giuliana; Guardamagna, Ornella; Iannuzzo, Gabriella; Giuseppe, Mandraffino; Maroni, Lorenzo; Mombelli, Giuliana; Muntoni, Sandro; Parati, Gianfranco; Angelina, Passaro; Pederiva, Cristina; Pisciotta, Livia; Pujia, Arturo; Francesco, Purrello; Rita, Roscini Anna; Sarzani, Riccardo; Suppressa, Patrizia; Pablo, Werba Josè; Zambon, Sabina; Grazia, Zenti Maria; Massimiliano, Allevi; Auricchio, Renata; Baldera, Davide; Banderali, Giuseppe; Bruzzi, Patrizia; Bucci, Marco; Sabrina, Buonuomo Paola; Elena, Capra Maria; Baldassarre, Cefalù Angelo; Covetti, Giuseppe; D’Addato, Sergio; Donata, Di Taranto Maria; Roberto, Franceschi; Fimiani, Fabio; Simonetta, Genovesi; Grigore, Liliana; Lupattelli, Graziana; Sara, Madaghiele; Massini, Giulia; Minicocci, Ilenia; Montalcini, Tiziana; Nascimbeni, Fabio; Chiara, Pavanello; Massimo, Perla Francesco; Gaia, Peroni; Sani, Elena; Scicali, Roberto; Arianna, Toscano; Battista, Vigna Giovanni; Alberto, Zambon; Luigi, Catapano Alberico; Casula, Manuela; Galimberti, Federica; Gazzotti, Marta; Olmastroni, Elena; Zampoleri, V.

doi:10.1016/j.atherosclerosis.2022.04.021

Cited by 11 publications

(5 citation statements)

References 41 publications

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“…We also found that in 1 out of 5 subjects with FH/M−, 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 were detected, a frequency that was double compared with subjects with FH/M+. Some studies 4 , 18 , 19 , 20 reported higher lp(a) levels in subjects with FH/M− compared with those with FH/M+; with a similar approach, our analysis described difference in LPA genotype in the population with FH. This genetic feature, associated with higher lp(a) levels, determined an increase in the reported LDL‐C levels, although comparisons were not statistically significant.…”

Section: Discussionsupporting

confidence: 66%

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Olmastroni

Gazzotti

Averna

et al. 2023

JAHA

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Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M−) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk‐increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M− and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M− also had lower mean levels of pretreatment low‐density lipoprotein cholesterol than individuals with FH/M+ ( t test for difference in means between FH/M− and FH/M+ groups <0.0001); however, subjects with FH/M− and lp(a) score ≥1 had higher mean (SD) pretreatment low‐density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M− and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low‐density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low‐density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH.

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Section: Discussionsupporting

confidence: 66%

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Olmastroni

Gazzotti

Averna

et al. 2023

JAHA

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“…Lipoprotein(a) should be regarded as a mimicking and modifier factor of the hypercholesterolemia phenotype as recently reported by Marco-Benedí et al [ 75 ]. A sub-study of the Italian LIPIGEN registry of genetic dyslipidemias reported that high Lipoprotein(a) levels were associated with a positive history of ASCVD in FH children [ 76 ]. The potential of including Lipoprotein(a) as an integration of the clinical FH diagnosis was recently reviewed [ 77 ].…”

Section: Genetics and Molecular Basismentioning

confidence: 99%

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

Taranto

Fortunato

2023

IJMS

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Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis.

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“…A recent study confirmed the absence of significant differences in early vascular aging in a group of young people with elevated Lp(a) compared with a control group [ 75 ]. Recently, the Italian LIPIGEN network demonstrated in a group of 653 Caucasian children and adolescents aged 2 to 17 years with clinical and/or genetic diagnosis of familial hypercholesterolemia that individuals with the highest Lp(a) values were also those with a higher prevalence of early cardiovascular events in first- or second-degree gentiles [ 76 ]. Finally, a very new publication [ 77 ] considered two studies in which the relationship between Lp(a) values in young people aged 9 to 24 years and 8 to 17 years and the incidence of cardiovascular events at the mean age of 47 years was assessed.…”

Section: Lp(a) In Children and Adolescentsmentioning

confidence: 99%

Evidence and Uncertainties on Lipoprotein(a) as a Marker of Cardiovascular Health Risk in Children and Adolescents

et al. 2023

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Lipoprotein(a) (Lp(a)) is made up of apoprotein(a) (apo(a)) and an LDL-like particle. The LPA gene encodes apo(a) and thus determines the characteristics and amount of apo(a) and Lp(a). The proportion of Lp(a) in each individual is genetically determined and is only minimally modifiable by the environment or diet. Lp(a) has important pro-atherosclerotic and pro-inflammatory effects. It has been hypothesized that Lp(a) also has pro-coagulant and antifibrinolytic actions. For these reasons, high Lp(a) values are an important independent risk factor for cardiovascular disease and calcific aortic valve stenosis. Numerous studies have been performed in adults about the pathophysiology and epidemiology of Lp(a) and research is under way for the development of drugs capable of reducing Lp(a) plasma values. Much less information is available regarding Lp(a) in children and adolescents. The present article reviews the evidence on this topic. The review addresses the issues of Lp(a) changes during growth, the correlation between Lp(a) values in children and those in their parents, and between Lp(a) levels in children, and the presence of cardiovascular disease in the family. Gaining information on these points is particularly important for deciding whether Lp(a) assay may be useful for defining the cardiovascular risk in children, in order to plan a prevention program early.

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Lipoprotein(a) and family history for cardiovascular disease in paediatric patients: A new frontier in cardiovascular risk stratification. Data from the LIPIGEN paediatric group

Cited by 11 publications

References 41 publications

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

Evidence and Uncertainties on Lipoprotein(a) as a Marker of Cardiovascular Health Risk in Children and Adolescents

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