: 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; Catapano, Alberico Luigi; Casula, Manuela; Stefano, Bertolini; Sebastiano, Calandra; Patrizia, Tarugi; Fabio, Pellegatta; Andrea, Bartuli; Andrea, Benso; Giacomo, Biasucci; Gianni, Biolo; Luca, Bonanni; Katia, Bonomo; Claudio, Borghi; Antonio Carlo Bossi, ; Adriana, Branchi; Paolo, Calabrò; Francesca, Carubbi; Francesco, Cipollone; Nadia, Citroni; Maria Del Ben, ; Massimo, Federici; Claudio, Ferri; Anna Maria Fiorenza, ; Andrea, Giaccari; Ornella, Guardamagna; Arcangelo, Iannuzzi; Iannuzzo, Gabriella; Lorenzo, Iughetti; Graziana, Lupattelli; Alessandro, Lupi; Giuseppe, Mandraffino; Rossella, Marcucci; Lorenzo, Maroni; Giuliana, Mombelli; Sandro, Muntoni; Valerio, Pecchioli; Cristina, Pederiva; Antonio, Pipolo; Livia, Pisciotta; Antonio, Pujia; Francesco, Purrello; Elena, Repetti; Carlo, Sabbà; Riccardo, Sarzani; Chiara, Trenti; Giovanni Battista Vigna, ; Josè Pablo Werba, ; Sabina, Zambon; Maria Grazia Zenti, ; Alessia Di Costanzo, ; Fortunato, Giuliana; Rossella, Spina; Davide, Baldera; Giuseppe, Banderali; Francesco, Baratta; Guglielmo, Beccuti; Sandra, Bertocco; Patrizia, Bruzzi; Marco, Bucci; Paola Sabrina Buonuomo, ; Maria Elena Capra, ; Iris, Cardolini; Angelo Baldassarre Cefalù, ; Maria, Cinquegrani; Emanuela, Colombo; Giuseppe, Covetti; Anna Laura Cremonini, ; Ada, Cutolo; Sergio, D'Addato; Vincenzo, D'Ambrosio; Giuseppe De Corrado, ; Chiara Di Pentima, ; Fabio, Fimiani; Gentile, Marco; Omar, Ghirardello; Betti, Giusti; Davide, Grassi; Liliana, Grigore; Giulia, Massini; Giancarla, Meregalli; Ilenia, Minicocci; Simona, Moffa; Tiziana, Montalcini; Fabio, Nascimbeni; Emanuele Alberto Negri, ; Chiara, Pavanello; Lucia, Prati; Anna Rita Roscini, ; Elena, Sani; Alon, Schaffer; Roberto, Scicali; Patrizia, Suppressa; Michele, Tedeschi; Pierandrea, Vinci; Enzo, Manzato; Elena, Tragni; Veronica, Zampoler. - In: JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE. - ISSN 2047-9980. - (2022). [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
Arca, Marcello;Averna, Maurizio;Gabriella Iannuzzo;Giuliana Fortunato;Marco Gentile;
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.
