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 have been implicated in familial combined hyperlipidemia (FCHL). However, their contribution might have been influenced by diagnostic criteria. This study was aimed to reassess the frequency of rare and common variants in LDLR and LPL in FCHL individuals classified with stringent criteria.


METHODS
LDLR and LPL were resequenced in 208 FHCL and 171 controls. Variants were classified as loss- (LOF) or gain-of-function (GOF) based upon in silico prediction, familial segregation and available functional data.


RESULTS
Eight LOF variants were detected in LDLR, 6 of which were missense and 2 were predicted to disrupt normal splicing; all were present at heterozygous state. They were found in 10 FCHL but not in controls, thus indicating that 4.8% of FCHL individuals should be reclassified as FH. LDL-C (positive) and BMI (negative) were the strongest predictors of LDLR mutations with LDL-C 181 mg/dl being the best threshold for diagnosing the presence of dysfunctional LDLR alleles. The cumulative prevalence of definite LPL defective alleles (1 rare and 2 common heterozygous missense variants) was comparable between FCHL and controls (10.1% vs. 10.5%). Conversely, the LPL GOF variant p.Ser474* showed a lower frequency in FCHL than in controls (13.5% vs. 24.0%, p = 0.008). Overall, LOF LPL variants did not show a TG-modulating effect.


CONCLUSIONS
Our findings indicate that, in well characterized FCHL individuals, variants in LDLR and LPL provide a small contribution to this dyslipidemia, thus limiting the need for such genetic testing.
Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy.
Ilenia
I
Minicocci
Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy.
Cristina
C
Prisco
Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy.
Anna
A
Montali
Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy.
Alessia
A
Di Costanzo
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Fabrizio
F
Ceci
Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy.
Giovanni
G
Pigna
Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy. Electronic address: marcelloarca@libero.it.
Marcello
M
Arca
D000328:Adult; D000368:Aged; D000483:Alleles; D017398:Alternative Splicing; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000201:enzymology* / Q000235:genetics*; D007558:Italy; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*
C573412:LDLR protein, human; D011973:Receptors, LDL; C548261:LPL protein, human; D008071:Lipoprotein Lipase
Association study; Familial combined hyperlipidemia; LDLR gene; LPL gene; Polymorphisms; Rare mutations; Resequencing