Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia
Authors: Olmastroni Elena , Gazzotti Marta , Averna Maurizio , Arca Marcello , Tarugi Patrizia , Calandra Sebastiano , Bertolini Stefano , Catapano Alberico L. , Casula Manuela , Arca Marcello , D’Erasmo Laura , Averna Maurizio , Cefalù Angelo Baldassare , Bartuli Andrea , Buonuomo Paola Sabrina , Benso Andrea , Beccuti Guglielmo , Biasucci Giacomo , Capra Maria Elena , Biolo Gianni , Vinci Pierandrea , Bonanni Luca , Borghi Claudio , D’Addato Sergio , Bossi Antonio Carlo , Meregalli Giancarla , Branchi Adriana , Calabrò Paolo , Carubbi Francesca , Nascimbeni Fabio , Cipollone Francesco , Bucci Marco , Citroni Nadia , Del Ben Maria , Baratta Francesco , Federici Massimo , Montagna Martina , Ferri Claudio , Notargiacomo Serena , Fiorenza Anna Maria , Colombo Emanuela , Fortunato Giuliana , Di Taranto Maria Donata , Giaccari Andrea , Moffa Simona , Giorgino Francesco , Di Molfetta Sergio , Guardamagna Ornella , De Sanctis Luisa , Iannuzzi Arcangelo , Cavallaro Raimondo , Iannuzzo Gabriella , Gentile Marco , Iughetti Lorenzo , Bruzzi Patrizia , Lia Salvatore , Lupi Alessandro , Mandraffino Giuseppe , Toscano Arianna , Marcucci Rossella , Berteotti Martina , Maroni Lorenzo , Locatelli Fabiana , Montalcini Tiziana , Mombelli Giuliana , Muntoni Sandro , Baldera Davide , Parati Gianfranco , Passaro Angelina , Pecchioli Valerio , Pederiva Cristina , Banderali Giuseppe , Pipolo Antonio , D’Elia Debora , Pirro Matteo , Bianconi Vanessa , Pisciotta Livia , Formisano Elena , Purrello Francesco , Scicali Roberto , Repetti Elena , Cantino Elena , Rinaldi Elisabetta , Sani Elena , Sarzani Riccardo , Spannella Francesco , Sbrana Francesco , Dal Pino Beatrice , Suppressa Patrizia , Cocco Veronica , Trenti Chiara , Negri Emanuele Alberto , Werba Josè Pablo , Romandini Alessandra , Zambon Sabina , Zambon Alberto , Zenti Maria Grazia , Fainelli Giulia , Pellegatta Fabio , Grigore Liliana , Bonomo Katia , Capatti Eleonora , Cutolo Ada , Fimiani Fabio , Genovesi Simonetta , Inchiostro Sandro , Pavanello Chiara , Pujia Roberta , Schaffer Alon , Bertolini Stefano , Calandra Sebastiano , Catapano Alberico Luigi , Casula Manuela , Olmastroni Elena , Tarugi Patrizia , Gazzotti Marta , Galimberti Federica 
Published: May 2023

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.