Genetic contribution to lipid target achievement with statin therapy: a prospective study.

Statin therapy response is highly variable. Variants of lipid metabolism genes and statin pharmacokinetic modulators could play a role, however, the impact of most of these variants remains unconfirmed. A prospective and multicenter study included 252 patients was carried out in order to assess, according to achievement of LDL-C or non-HDL-C therapeutic targets and quantitative changes in lipid profiles, the impact of CETP, ABCA1, CYP2D6, and CYP2C9 gene candidate variants on the simvastatin, atorvastatin, and rosuvastatin response. Patients carrier ABCA1 rs2230806 and CYP2D6*3 variants are less likely to achieve therapeutic lipid targets (p = 0.020, OR = 0.59 [0.37, 0.93]; p = 0.040, OR = 0.23 [0.05, 0.93], respectively). Among CETP variants, rs708272 was linked to a 10.56% smaller reduction in LDL-C with rosuvastatin (95% CI = [1.27, 19.86] %; p = 0.028). In contrast, carriers of rs5882 had a 13.33% greater reduction in LDL-C (95% CI = [25.38, 1.28]; p = 0.032). If these findings are confirmed, ABCA1, CYP2D6, and CETP genotyping could be used to help predict which statin and dosage is appropriate in order to improve personalized medicine.

KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment.

INTRODUCTION: The therapeutic response to statins has a high interindividual variability with respect to reductions in plasma LDL-cholesterol (c-LDL) and increases in HDL cholesterol (c-HDL). Many studies suggest that there is a relationship between the rs20455 KIF6 gene variant (c.2155T> C, Trp719Arg) and a lower risk of cardiovascular disease in patients being treated with statins. AIM: The aim of this study was to investigate whether or not the c.2155T> C KIF6 gene variant modulates the hypercholesteremic effects of treatment with simvastatin, atorvastatin, or rosuvastatin. MATERIALS AND METHODS: This was a prospective, observational and multicenter study. Three hundred and forty-four patients who had not undergone prior lipid-lowering treatment were recruited. Simvastatin, atorvastatin or rosuvastatin were administered. Lipid profiles and multiple clinical and biochemical variables were assessed before and after treatment. RESULTS: The c.2155T> C variant of the KIF6 gene was shown to influence physiological responses to treatment with simvastatin and atorvastatin. Patients who were homozygous for the c.2155T> C variant (CC genotype, ArgArg) had a 7.0% smaller reduction of LDL cholesterol levels (p = 0.015) in response to hypolipidemic treatment compared to patients with the TT (TrpTrp) or CT (TrpArg) genotype. After pharmacological treatment with rosuvastatin, patients carrying the genetic variant had an increase in c-HDL that was 21.9% lower compared to patients who did not carry the variant (p = 0.008). CONCLUSION: Being a carrier of the c.2155T> C variant of the KIF6 gene negatively impacts patient responses to simvastatin, atorvastatin or rosuvastatin in terms of lipid lowering effect. Increasing the intensity of hypolipidemic therapy may be advisable for patients who are positive for the c.2155T> C variant.

APOE Variants E2, E3, and E4 Can Be Miscalled By Classical PCR-RFLP When The Christchurch Variant Is Also Present.

BACKGROUND: The APOE Christchurch (APOECh) is a rare variant (c.543C>A) in codon 154. It was first described in an E2 patient with type III dyslipidemia, and thus initially called E2Ch. Its prevalence and the lipid profile of carriers remain unclear. METHODS: E2, E3, and E4 screening for the APOE gene was performed by PCR-RFLP. The rare APOECh variant was firstly found after detecting an unexpected 109 base-pair band in the high-resolution agarose gel electrophoresis leading to a genotype misinterpretation: the presence of APOECh alters the restriction-bands pattern. To confirm the Ch variant, a second PCR-RFLP method was specifically designed to detect this variant and Sanger sequencing was also performed for all positive samples. RESULTS: We identified 12 unrelated subjects for the APOECh among a cohort of 2,560 patients: nine E3/E3Ch, two E3Ch/E4, and one E2/E3Ch or E2Ch/E3. The frequency of the variant is 0.4% in our study population, which represents the highest percentage published so far. If there is a 109 bp band, it is easy to recognize the presence of the variant. However, in APOE routine genotyping, an E4Ch allele is indistinguishable from a standard E3. Therefore, E4Ch alleles might be underrepresented in the results. CONCLUSION: We recommend APOE exon 4 sequencing to unequivocally detect the common three variants E2, E3, and E4 and the rare variants as well, to find out the real role they play in atherosclerosis and to estimate its real frequency which is nowadays unclear, in part by the small number of cases identified.

HLA-B*57: 01 genotyping in the prevention of hypersensitivity to abacavir: 5 years of experience.

INTRODUCTION: Most of the cost-effectiveness analyses are based on estimations to make decisions on the future implementation of a test. However, the model should be verified with real data to prove that previous estimations have been successfully fulfilled. OBJECTIVE: To study the economic impact of the systematic HLA-B*57:01 genotyping in preventing hypersensitivity reactions (HSRs) in the patient population of a tertiary-care hospital treated with abacavir (ABC) using retrospective data of 5 years of experience. METHODS: A retrospective study was carried out with two cohorts including 780 and 473 patients before and after the implementation of the systematic HLA-B*57:01 genotyping before ABC treatment. Cost-effectiveness analysis was carried out by the parameter 'cost per HSR avoided'. The clinical utility of the test was verified by evaluating the differences in HSR incidence between both cohorts. Finally, a sensitivity analysis including all variables was carried out. RESULTS: In the population studied, systematic genotyping represents an additional cost of &OV0556;306 per HSR avoided. In the sensitivity analysis, pharmacological therapy cost is the major influencing factor found in the estimation of the 'cost per HSR avoided'. In terms of clinical utility, the incidence ratio was 0.040 (95% confidence interval 0.0009-0.2399) and statistically significant differences were found between both groups (P=1.40×10). CONCLUSION: Retrospective data from 5 years of experience have confirmed the cost-effectiveness of the systematic genotyping in candidate patients for ABC therapy, and have shown that cost-effectiveness is a dynamic parameter closely linked to allele prevalence and pharmacological therapy costs.