Abstract / Summary
Familial hypercholesterolemia (FH) is caused by an impaired ability to clear circulating low-density lipoprotein (LDL-C) particles due to a defective low-density lipoprotein receptor (LDLR). FH significantly increases cardiovascular risk (CVR). Although conventional lipid parameters are essential for diagnosing FH, they do not fully capture the metabolic impact of inherited LDLR dysfunction. This study aimed to characterize the plasma lipidomic phenotype associated with pathogenic LDLR variants in individuals with suspected FH. Forty-four participants underwent genetic testing for LDLR, apolipoprotein B-100 (APOB), and protein convertase subtilisin/kexin type 9 (PCSK9). After excluding three carriers of the APOB p.Arg3527Gln variant, the comparative lipidomic analysis included 41 participants. The study included 17 carriers of pathogenic LDLR variants and 24 participants without a detected pathogenic variant in the tested panel. We performed plasma lipidomic profiling using flow-injection analysis coupled with high-resolution tandem mass spectrometry (FIA-MS/MSALL) without chromatographic separation. Lipid annotation and data processing were performed using LipidView software, and lipidomic measurements were expressed as relative signal abundances derived from mass spectrometry (MS) peak intensities. Statistical analyses included Mann–Whitney U tests with false discovery rate (FDR) correction across the analyzed lipid features. Exploratory multivariable logistic regression and receiver operating characteristic (ROC) analyses were also performed. There were no differences in conventional lipid parameters between genetically confirmed LDLR variant carriers and participants without a detected pathogenic variant in the tested panel. At the nominal level (unadjusted p < 0.05), lipidomic profiling revealed differences in glycerophospholipid (GP)related analytical features between groups. However, no individual lipid feature remained statistically significant after full-family FDR correction. Among (GPs), 69 feature records (16.3%) showed nominal between-group differences, predominantly lower abundance in LDLR variant carriers. The most consistent nominal alterations were observed in features annotated as phosphatidylinositol triphosphates (PIP3) and N-acyl phosphatidylethanolamines (NAPE). Among the analyzed fatty acyls (FAs), 72.7% showed nominally lower relative abundance in LDLR variant carriers. We used exploratory multivariable models to identify GP and FA -related features associated with the detected pathogenic LDLR variant status. The models showed within-cohort discrimination. However, these models were developed and evaluated in the same small cohort after data-driven variable selection. They were not externally validated. Therefore, the findings should be interpreted as hypothesis-generating and do not establish diagnostic performance, clinical utility, or functional pathway impairment. Further validation in larger cohorts using targeted lipidomics with chromatographic separation is necessary.