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
Authors: Olmastroni Elena , Gazzotti Marta , Arca Marcello , Averna Maurizio , Pirillo Angela , Catapano Alberico Luigi , Casula Manuela , Bertolini Stefano , Calandra Sebastiano , Tarugi Patrizia , Pellegatta Fabio , Bartuli Andrea , Benso Andrea , Biasucci Giacomo , Biolo Gianni , Bonanni Luca , Bonomo Katia , Borghi Claudio , Bossi Antonio Carlo , Branchi Adriana , Calabrò Paolo , Carubbi Francesca , Cipollone Francesco , Citroni Nadia , Del Ben Maria , Federici Massimo , Ferri Claudio , Fiorenza Anna Maria , 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 , Vigna Giovanni Battista , Werba Josè Pablo , Zambon Sabina , Zenti Maria Grazia , Di Costanzo Alessia , Fortunato Giuliana , Spina Rossella , Baldera Davide , Banderali Giuseppe , Baratta Francesco , Beccuti Guglielmo , Bertocco Sandra , Bruzzi Patrizia , Bucci Marco , Buonuomo Paola Sabrina , Capra Maria Elena , Cardolini Iris , Cefalù Angelo Baldassarre , Cinquegrani Maria , Colombo Emanuela , Covetti Giuseppe , Cremonini Anna Laura , 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 , Negri Emanuele Alberto , Pavanello Chiara , Prati Lucia , Roscini Anna Rita , Sani Elena , Schaffer Alon , Scicali Roberto , Suppressa Patrizia , Tedeschi Michele , Vinci Pierandrea , Manzato Enzo , Tragni Elena , Zampoleri Veronica 
Published: March 2022

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.