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Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment
A-L García-Otín1, F Civeira, R Aristegui
1Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain.
Insights
Apolipoprotein E gene promoter polymorphism influences lipid-lowering drug efficacy in combined hyperlipidemia (CHL) patients. The -491A/T polymorphism affects atorvastatin and bezafibrate responses, impacting treatment variability.
Area of Science:
- Pharmacogenomics
- Cardiovascular Genetics
- Lipid Metabolism
Background:
- Combined hyperlipidemia (CHL) is a common dyslipidemia requiring lipid-lowering medications.
- Genetic factors, including polymorphisms, can influence the effectiveness of lipid-lowering therapies.
- Investigating gene variants in apolipoprotein E (apo E), lipoprotein lipase (LPL), and apo CIII may clarify inter-individual drug responses.
Purpose of the Study:
- To determine if common polymorphisms and mutations in apo E, LPL, and apo CIII genes affect patient responses to atorvastatin and bezafibrate.
- To analyze the influence of specific apo E gene promoter polymorphisms (-491A/T and -219T/G) on drug efficacy in CHL patients.
Main Methods:
- 116 CHL patients from the ATOMIX study were randomized to atorvastatin or bezafibrate.
- Genotyping included Apolipoprotein E, apo E promoter polymorphisms (-491A/T, -219T/G), apo CIII Sst I polymorphism, and LPL mutations (D9N, N291S) using PCR and restriction digestion.
Main Results:
- The -491A/T polymorphism in the apo E gene promoter significantly influenced responses to both atorvastatin and bezafibrate.
- Patients with the -491T allele showed a greater LDL-cholesterol reduction with atorvastatin (-35% vs. -27%, P=0.037).
- Carriers of the -491T allele on bezafibrate exhibited reduced triglyceride lowering compared to non-carriers (-23% vs. -39%, P=0.05).
Conclusions:
- The -491A/T polymorphism in the apo E gene promoter modulates the lipid-lowering effects of atorvastatin and bezafibrate in CHL.
- This genetic influence may explain variations in patient responses to these lipid-lowering drugs.
- Identifying this polymorphism could aid in personalized CHL management strategies.
Background:
Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL.
Design:
One hundred and sixteen subjects participating in the ATOMIX study (Atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion.
Results:
Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05).
Conclusions:
In our study, the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients. Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.