Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects

BackgroundThe proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs.ObjectiveTo investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects.MethodsPCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction.ResultsFrequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates (P = .059). The 670G allele was associated with high basal levels of LDL cholesterol (P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups (P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes.

Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in theregulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation ofLDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipidsand may contribute to the variability of the response to cholesterol-lowering drugs.OBJECTIVE: To investigate the influence of PCSK9 variants on plasma lipid profile and response toatorvastatin in Brazilian subjects.METHODS: PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasmalipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patientswith indication for cholesterol-lowering drug therapy (n 5 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction.RESULTS: Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logisticregression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemiaafter adjustment for covariates (P 5 .059). The 670G allele was associated with high basal levels ofLDL cholesterol (P 5 .03) in HC patients using the extreme discordant phenotype method. Noassociation tests were performed for R46L variant because of its very low frequency, whereas theI474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variabilityon plasma lipids in both NL and HC groups (P ..05). LDL cholesterol reduction in response to atorvastatinwas not influenced by PCSK9 genotypes or haplotypes.CONCLUSIONS: PCSK9 E670G polymorphism but not I474V contributes to the variability onplasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influenceon cholesterol-lowering response to atorvastatin. 2014 National Lipid Association. All rights reserved.

Differentiation of african components of ancestry to stratify groups in a Case–control study of a brazilian urban population

Background: Balancing the subject composition of case and control groups to create homogenous ancestries between each group is essential for medical association studies. Methods: We explored the applicability of single-tube 34-plex ancestry informative markers (AIM) single nucleotide polymorphisms (SNPs) to estimate the African Component of Ancestry (ACA) to design a future case-control association study of a Brazilian urban sample. Results: One hundred eighty individuals (107 case group; 73 control group) self-described as white, brown-intermediate or black were selected. The proportions of the relative contribution of a variable number of ancestral population components were similar between case and control groups. Moreover, the case and control groups demonstrated similar distributions for ACA 0.50 categories. Notably a high number of outlier values (23 samples) were observed among individuals with ACA <0.25. These individuals presented a high probability of Native American and East Asian ancestral components; however, no individuals originally giving these self-described ancestries were observed in this study. Conclusions: The strategy proposed for the assessment of ancestry and adjustment of case and control groups for an association study is an important step for the proper construction of the study, particularly when subjects are taken from a complex urban population. This can be achieved using a straight forward multiplexed AIM-SNPs assay of highly discriminatory ancestry markers.

Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A>G Variant Is Determinant of Increased Atorvastatin Response

Aims: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. Material and Methods: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected andOPEN ACCESStreated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot® and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (−71T>C) gene polymorphisms were identified by TaqMan® Real-time PCR. Results: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3–8.0, p G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.