LRP1 Gene Polymorphisms Are Associated With Premature Risk of Cardiovascular Disease in Patients With Familial Hypercholesterolemia

Introduction and objectivesLRP1 gene overexpression in atherosclerotic plaque is associated with increased lipid uptake through the vascular wall. The aim of the study was to analyze whether LRP1 modulates the genetic risk of developing premature cardiovascular disease in familial hypercholesterolemia, using single nucleotide polymorphism association analysis.MethodsTen polymorphisms of the LRP1 gene (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164, and rs35282763) were genotyped in 339 patients (77 with premature cardiovascular disease and 262 without) in the SAFEHEART study.ResultsThe c.677C>T (rs1799986) polymorphism showed a significant association with premature cardiovascular disease after adjusting by sex, age, body mass index, and the effect of the low-density lipoprotein receptor mutation in the dominant model (CT+TT vs CC: odds ratio=1.94; 95% confidence interval, 1.08-3.48; P=.029). Similar results were observed after increasing the sample to 648 subjects (133 with premature cardiovascular disease vs 515 without [odds ratio=1.83; 95% confidence interval, 1.16-2.88; P=.011]).ConclusionsThe c.677C>T polymorphism is associated with increased rates of premature cardiovascular disease in familial hypercholesterolemia. Although we were unable to show that this polymorphism was involved in the alteration of normal mRNA splicing patterns, the possibility that it is in strong linkage disequilibrium with another functional polymorphism cannot be ruled out and would explain the cause-effect relationship with cardiovascular disease risk in this population. Further studies are needed to replicate the results and to localize the putative genetic variants associated with this polymorphism.

ResumenIntroducción y objetivosLa expresión del gen LRP1, muy acentuada en la placa aterosclerótica, se asocia con un aumento en la incorporación de lípidos por la pared vascular. Nuestro objetivo es analizar si el gen LRP1 modula el riesgo genético de aparición de enfermedad cardiovascular prematura en pacientes con hipercolesterolemia familiar mediante asociación de polimorfismos.MétodosSe genotipificaron 10 polimorfismos de un solo nucleótido del gen LRP1 (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164 y rs35282763) en 339 pacientes (77 con enfermedad cardiovascular y 262 sin enfermedad) pertenecientes al estudio SAFEHEART.ResultadosSe halló una asociacion significativa con el polimorfismo c.677C>T (rs1799986) tras ajustar por sexo, edad, índice de masa corporal y efecto de la mutación del receptor de lipoproteínas de baja densidad con el modelo dominante (CT+TT frente a CC: odds ratio = 1,94; intervalo de confianza del 95%, 1,08-3,48; p = 0,029). Tras ampliar la población a 648 individuos (133 con enfermedad y 515 sin ella), se obtuvieron resultados similares (odds ratio = 1,83; intervalo de confianza del 95%, 1,16-2,88; p = 0,011).ConclusionesEl polimorfismo c.677C>T se asocia con aumento del riesgo de enfermedad cardiovascular prematura en la hipercolesterolemia familiar. Aunque su implicación en la alteración de un patrón normal de procesamiento del ARNm no se ha corroborado, no se descarta que dicho polimorfismo se halle en desequilibrio de ligamento con otro polimorfismo funcional en el que resida la relación causa-efecto con la enfermedad cardiovascular. Serían necesarios más estudios para corroborar los resultados y localizar las variantes genéticas relacionadas con dicho polimorfismo implicadas en conferir riesgo de enfermedad cardiovascular.