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

Abstract

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.

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

“…These data suggest that high Lp(a) values may be a greater risk factor than carrying a genetic mutation causing heterozygous FH [ 79 ]. On the sidelines, we can mention that recently, the analysis of data from the LIPIGEN network in adults confirmed that very high Lp(a) levels can explain at least part of the clinical diagnoses of FH in subjects with very high-LDL cholesterol values and negative analysis for causative genes of this disease [ 80 ].…”

Impact of 12-SNP and 6-SNP Polygenic Scores on Predisposition to High LDL-Cholesterol Levels in Patients with Familial Hypercholesterolemia

“…In fact, a recent study conducted by the Italian network LIPIGEN showed that the correction of LDL-c levels for lipoprotein(a) levels resulted in a lower percentage of FH patients with LDL-c levels ≥190 mg/dL [14].…”