Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): A reappraisal by using a resequencing approach

Background:Defective low-density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) alleles havebeen implicated in familial combined hyperlipidemia (FCHL). However, their contribution might havebeen influenced by diagnostic criteria. This study was aimed to reassess the frequency of rare andcommon variants inLDLRandLPLin FCHL individuals classified with stringent criteria.Methods: LDLRandLPLwere resequenced in 208 FHCL and 171 controls. Variants were classified as loss-(LOF) or gain-of-function (GOF) based uponin silicoprediction, familial segregation and availablefunctional data.Results:Eight LOF variants were detected inLDLR, 6 of which were missense and 2 were predicted todisrupt normal splicing; all were present at heterozygous state. They were found in 10 FCHL but not incontrols, thus indicating that 4.8% of FCHL individuals should be reclassified as FH. LDL-C (positive) andBMI (negative) were the strongest predictors ofLDLRmutations with LDL-C 181 mg/dl being the bestthreshold for diagnosing the presence of dysfunctionalLDLRalleles. The cumulative prevalence of def-initeLPLdefective alleles (1 rare and 2 common heterozygous missense variants) was comparable be-tween FCHL and controls (10.1% vs. 10.5%). Conversely, theLPLGOF variant p.Ser474* showed a lowerfrequency in FCHL than in controls (13.5% vs. 24.0%, p¼0.008). Overall, LOFLPLvariants did not show aTG-modulating effect.Conclusions:Ourfindings indicate that, in well characterized FCHL individuals, variants inLDLRandLPLprovide a small contribution to this dyslipidemia, thus limiting the need for such genetic testing.©2015 Elsevier Ireland Ltd. All rights reserved