Lipid-lowering response of the HMG-CoA reductase inhibitor fluvastatin is influenced by polymorphisms in the low-density lipoprotein receptor gene in Brazilian patients with primary hypercholesterolemia

Abstract

Although the efficacy of fluvastatin (HMG-CoA reductase inhibitor) in the treatment of primary hypercholesterolemia is well documented, a wide interindividual variation treatment response has been observed. We have studied the possible role of the AvaII (exon 13), HincII (exon 12), and PvuII (intron 15) polymorphisms at the low-density lipoprotein receptor (LDLR) gene on lipid-lowering response in 55 patients (36 to 70 years old) with primary hypercholesterolemia treated with fluvastatin for 16 weeks. LDLR genotypes were determined by PCR-RFLP. The results indicate that the AvaII and PvuII polymorphisms influence the cholesterol-lowering response of the HMG-CoA reductase inhibitor Fluvastatin. Patients carrying A+A+ (AvaII) or P1P1 (PvuII) homozygous genotypes presented lower reduction in total cholesterol, LDL-C and apolipoprotein B levels after 16 weeks of treatment with fluvastatin, when compared to other genotypes (P<0.05). Our data also support the previous assumption that the AvaII, HincII, and PvuII polymorphisms of the LDLR gene are associated with variation of serum cholesterol levels. Therefore, the identification of the LDLR genetic profile may provide better prediction of a patient's clinical response to fluvastatin.

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels

“…8,11,27 However, this rate was different from the allele frequency found in Chilean Amerindian hypercholesterolemic subjects (0.44) from southern Chile, healthy Caucasian Brazilian individuals, and Chinese population. 7,[9][10][11] The analysis of PCSK9 mutated allele (G) frequency was 0.03, similar to the previously described for healthy and coronary disease patients from southern Chile, American Indians, European population, European elderly individuals with vascular disease, and Chinese population. 17,19,21,24,28 The difference in LDLR rs5925 allelic frequency in individuals from the north and south of Chile can be explained because the genetic composition of Chilean people is the result of a miscegenation process where larger Native American (42%) and European (55%) and smaller African (2%) ancestry contributed to admixed.…”

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels

“…8,11,27 However, this rate was different from the allele frequency found in Chilean Amerindian hypercholesterolemic subjects (0.44) from southern Chile, healthy Caucasian Brazilian individuals, and Chinese population. 7,[9][10][11] The analysis of PCSK9 mutated allele (G) frequency was 0.03, similar to the previously described for healthy and coronary disease patients from southern Chile, American Indians, European population, European elderly individuals with vascular disease, and Chinese population. 17,19,21,24,28 The difference in LDLR rs5925 allelic frequency in individuals from the north and south of Chile can be explained because the genetic composition of Chilean people is the result of a miscegenation process where larger Native American (42%) and European (55%) and smaller African (2%) ancestry contributed to admixed.…”

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

“…Greater Tc‐ and LDL‐lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc‐level lowering, p=0.043, and 4 mmol/l greater LDL‐level lowering, p=0.023, with absence of these restriction sites) . The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time …”

“…68 Greater Tc-and LDL-lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc-level lowering, p=0.043, and 4 mmol/l greater LDL-level lowering, p=0.023, with absence of these restriction sites). 70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established.…”

“…70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established. 67 Fluvastatin is readily absorbed from the small intestine but undergoes extensive first-pass metabolism to inactive metabolites by CYP2C9; to a lesser extent, CYP3A4, CYP2C8, and CYP2D6 are also involved in fluvastatin metabolism.…”

Pharmacogenetic implications in the management of metabolic diseases in Brazilian populations

“…Our group investigated the influence of three variants of the LDLR (Val653Val/AvaII, Asn591Asn/HincII and g.42716A>G/PvuII) in HC subjects. LDLR AvaII (A+A+) and PvuII (P1P1) genotypes were associated with high basal total cholesterol, LDL cholesterol and apoB plasma concentrations and reduced response of these lipids to fluvastatin (Salazar et al, 2000). Further we reported that the LDLR c.*52G>A variant, located in the 3´UTR, was associated with lower risk of hypercholesterolemia (OR: 0.58, 95%CI: 0.34-0.99, p=0.043) but not with response to atorvastatin (Zambrano et al, 2015).…”

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels

“…8,11,27 However, this rate was different from the allele frequency found in Chilean Amerindian hypercholesterolemic subjects (0.44) from southern Chile, healthy Caucasian Brazilian individuals, and Chinese population. 7,[9][10][11] The analysis of PCSK9 mutated allele (G) frequency was 0.03, similar to the previously described for healthy and coronary disease patients from southern Chile, American Indians, European population, European elderly individuals with vascular disease, and Chinese population. 17,19,21,24,28 The difference in LDLR rs5925 allelic frequency in individuals from the north and south of Chile can be explained because the genetic composition of Chilean people is the result of a miscegenation process where larger Native American (42%) and European (55%) and smaller African (2%) ancestry contributed to admixed.…”

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

“…Greater Tc‐ and LDL‐lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc‐level lowering, p=0.043, and 4 mmol/l greater LDL‐level lowering, p=0.023, with absence of these restriction sites) . The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time …”

“…68 Greater Tc-and LDL-lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc-level lowering, p=0.043, and 4 mmol/l greater LDL-level lowering, p=0.023, with absence of these restriction sites). 70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established.…”

“…70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established. 67 Fluvastatin is readily absorbed from the small intestine but undergoes extensive first-pass metabolism to inactive metabolites by CYP2C9; to a lesser extent, CYP3A4, CYP2C8, and CYP2D6 are also involved in fluvastatin metabolism.…”

Pharmacogenetic implications in the management of metabolic diseases in Brazilian populations

“…Our group investigated the influence of three variants of the LDLR (Val653Val/AvaII, Asn591Asn/HincII and g.42716A>G/PvuII) in HC subjects. LDLR AvaII (A+A+) and PvuII (P1P1) genotypes were associated with high basal total cholesterol, LDL cholesterol and apoB plasma concentrations and reduced response of these lipids to fluvastatin (Salazar et al, 2000). Further we reported that the LDLR c.*52G>A variant, located in the 3´UTR, was associated with lower risk of hypercholesterolemia (OR: 0.58, 95%CI: 0.34-0.99, p=0.043) but not with response to atorvastatin (Zambrano et al, 2015).…”

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels

“…8,11,27 However, this rate was different from the allele frequency found in Chilean Amerindian hypercholesterolemic subjects (0.44) from southern Chile, healthy Caucasian Brazilian individuals, and Chinese population. 7,[9][10][11] The analysis of PCSK9 mutated allele (G) frequency was 0.03, similar to the previously described for healthy and coronary disease patients from southern Chile, American Indians, European population, European elderly individuals with vascular disease, and Chinese population. 17,19,21,24,28 The difference in LDLR rs5925 allelic frequency in individuals from the north and south of Chile can be explained because the genetic composition of Chilean people is the result of a miscegenation process where larger Native American (42%) and European (55%) and smaller African (2%) ancestry contributed to admixed.…”

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

“…Greater Tc‐ and LDL‐lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc‐level lowering, p=0.043, and 4 mmol/l greater LDL‐level lowering, p=0.023, with absence of these restriction sites) . The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time …”

“…68 Greater Tc-and LDL-lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc-level lowering, p=0.043, and 4 mmol/l greater LDL-level lowering, p=0.023, with absence of these restriction sites). 70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established.…”

“…70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established. 67 Fluvastatin is readily absorbed from the small intestine but undergoes extensive first-pass metabolism to inactive metabolites by CYP2C9; to a lesser extent, CYP3A4, CYP2C8, and CYP2D6 are also involved in fluvastatin metabolism.…”

Pharmacogenetic implications in the management of metabolic diseases in Brazilian populations

“…Our group investigated the influence of three variants of the LDLR (Val653Val/AvaII, Asn591Asn/HincII and g.42716A>G/PvuII) in HC subjects. LDLR AvaII (A+A+) and PvuII (P1P1) genotypes were associated with high basal total cholesterol, LDL cholesterol and apoB plasma concentrations and reduced response of these lipids to fluvastatin (Salazar et al, 2000). Further we reported that the LDLR c.*52G>A variant, located in the 3´UTR, was associated with lower risk of hypercholesterolemia (OR: 0.58, 95%CI: 0.34-0.99, p=0.043) but not with response to atorvastatin (Zambrano et al, 2015).…”