Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice.
Twelve variants polygenic score for low-density lipoprotein cholesterol distribution in a large cohort of patients with clinically diagnosed familial hypercholesterolemia with or without causative mutations / Olmastroni, Elena; Gazzotti, Marta; Arca, Marcello; Averna, Maurizio; Pirillo, Angela; Luigi Catapano and Manuela Casula and the LIPIGEN Study Group† LIPIGEN Study Group†: Stefano Bertolini, Alberico; Calandra, Sebastiano; Tarugi, Patrizia; Pellegatta, Fabio; Bartuli, Andrea; Benso, Andrea; Biasucci, Giacomo; Biolo, Gianni; Bonanni, Luca; Bonomo, Katia; Borghi, Claudio; Carlo Bossi, Antonio; Branchi, Adriana; Calabrò, Paolo; Carubbi, Francesca; Cipollone, Francesco; Citroni, Nadia; DEL BEN, Maria; Federici, Massimo; Ferri, Claudio; Maria Fiorenza, Anna; Giaccari, Andrea; Guardamagna, Ornella; Iannuzzi, Arcangelo; Iannuzzo, Gabriella; Iughetti, Lorenzo; Lupattelli, Graziana; Lupi, Alessandro; Mandraffino, Giuseppe; Marcucci, Rossella; Maroni, Lorenzo; Mombelli, Giuliana; Muntoni, Sandro; Pecchioli, Valerio; Pederiva, Cristina; Pipolo, Antonio; Pisciotta, Livia; Pujia, Antonio; Purrello, Francesco; Repetti, Elena; Sabbà, Carlo; Sarzani, Riccardo; Trenti, Chiara; Battista Vigna, Giovanni; Pablo Werba, Josè; Zambon, Sabina; Grazia Zenti, Maria; DI COSTANZO, Alessia; Fortunato, Giuliana; Spina, Rossella; Baldera, Davide; Banderali, Giuseppe; Baratta, Francesco; Beccuti, Guglielmo; Bertocco, Sandra; Bruzzi, Patrizia; Bucci, Marco; Sabrina Buonuomo, Paola; Elena Capra, Maria; Cardolini, Iris; Baldassarre Cefalù, Angelo; Cinquegrani, Maria; Colombo, Emanuela; Covetti, Giuseppe; Laura Cremonini, Anna; Cutolo, Ada; D'Addato, Sergio; D'Ambrosio, Vincenzo; De Corrado, Giuseppe; Di Pentima, Chiara; Fimiani, Fabio; Gentile, Marco; Ghirardello, Omar; Giusti, Betti; Grassi, Davide; Grigore, Liliana; Massini, Giulia; Meregalli, Giancarla; Minicocci, Ilenia; Moffa, Simona; Montalcini, Tiziana; Nascimbeni, Fabio; Alberto Negri, Emanuele; Pavanello, Chiara; Prati, Lucia; Rita Roscini, Anna; Sani, Elena; Schaffer, Alon; Scicali, Roberto; Suppressa, Patrizia; Tedeschi, Michele; Vinci, Pierandrea; Manzato, Enzo; Tragni, Elena; Zampoleri, Veronica. - In: JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE. - ISSN 2047-9980. - 11:7(2022), pp. 1-14. [10.1161/JAHA.121.023668]
Twelve variants polygenic score for low-density lipoprotein cholesterol distribution in a large cohort of patients with clinically diagnosed familial hypercholesterolemia with or without causative mutations
Marcello Arca;Maria Del Ben;Alessia Di Costanzo;Francesco Baratta;Ilenia Minicocci;
2022
Abstract
Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
