CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population

<p>Abstract</p> <p>Background</p> <p>Recent studies have reported the clinical importance of <it>CYP2C19 </it>and <it>ABCB1 </it>polymorphisms in an individualized approach to clopidogrel treatment. The aims of this study were to evaluate the frequencies of <it>CYP2C19 </it>and <it>ABCB1 </it>polymorphisms and to identify the clopidogrel-predicted metabolic phenotypes according to ethnic groups in a sample of individuals representative of a highly admixtured population.</p> <p>Methods</p> <p>One hundred and eighty-three Amerindians and 1,029 subjects of the general population of 4 regions of the country were included. Genotypes for the <it>ABCB1</it>c.C3435T (rs1045642), <it>CYP2C19*2 </it>(rs4244285), <it>CYP2C19*3 </it>(rs4986893), <it>CYP2C19*4 </it>(rs28399504), <it>CYP2C19*5 </it>(rs56337013), and <it>CYP2C19*17 </it>(rs12248560) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis. The <it>CYP2C19*3</it>, <it>CYP2C19*4 </it>and <it>CYP2C19*5 </it>variants were genotyped in a subsample of subjects (300 samples randomly selected).</p> <p>Results</p> <p>The <it>CYP2C19*3 </it>and <it>CYP2C19*5 </it>variant alleles were not detected and the <it>CYP2C19*4 </it>variant allele presented a frequency of 0.3%. The allelic frequencies for the <it>ABCB1</it>c.C3435T, <it>CYP2C19*2 </it>and <it>CYP2C19*17 </it>polymorphisms were differently distributed according to ethnicity: Amerindian (51.4%, 10.4%, 15.8%); Caucasian descent (43.2%, 16.9%, 18.0%); Mulatto (35.9%, 16.5%, 21.3%); and African descent (32.8%, 20.2%, 26.3%) individuals, respectively. As a result, self-referred ethnicity was able to predict significantly different clopidogrel-predicted metabolic phenotypes prevalence even for a highly admixtured population.</p> <p>Conclusion</p> <p>Our findings indicate the existence of inter-ethnic differences in the <it>ABCB1 </it>and <it>CYP2C19 </it>variant allele frequencies in the Brazilian general population plus Amerindians. This information could help in stratifying individuals from this population regarding clopidogrel-predicted metabolic phenotypes and design more cost-effective programs towards individualization of clopidogrel therapy.</p

LPA rs10455872 polymorphism is associated with coronary lesions in Brazilian patients submitted to coronary angiography

Abstract\ud \ud Background\ud Polymorphisms in the LPA gene were associated with coronary artery disease (CAD). However, there are differences in the allelic frequencies, Lp(a) levels, and significant association with CAD according to ethnic groups. In this scenario, the main aim of this study was to assess the influence of the LPA polymorphisms on coronary lesions in Brazilian patients.\ud \ud \ud Methods\ud 1,394 consecutive patients submitted to coronary angiography to study suggestive CAD and twenty coronary segments were scored. Genotyping for the LPA rs10455872 and rs3798220 polymorphisms were performed by high resolution melting analysis.\ud \ud \ud Results\ud The frequencies of the rs10455872 G and rs3798220 C variant alleles were 6.4% and 6.2%, respectively. LPA rs10455872 G variant allele was associated with higher odds ratio of having coronary lesions in an adjusted model (OR = 2.02, 95% CI = 1.10-3.72, p = 0.02). Scores of coronary lesions (extension, severity, and Gensini scores) were significantly different among rs10455872 genotype groups. Coronary lesions was not associated with LPA rs3798220 (OR = 1.09, 95% CI = 0.67-1.76, p = 0.73) and scores of coronary lesions were not different among rs3798220 genotypes.\ud \ud \ud Conclusions\ud We confirmed the association of the LPA rs10455872 with CAD in a large sample of Brazilian patients. For the LPA rs3798220, our finding is consistent with studies which showed the lack of this genetic association.PCJL Santos is recipient of fellowship from FAPESP, Proc. 2013-09295-3, and\ud Proc. 2013-20614-3, Brazil. We also thank the patients who participated in the\ud study. The technical assistance of the Laboratory of Genetics and Molecular\ud Cardiology group is gratefully acknowledged

APOE polymorphism is associated with lipid profile, but not with arterial stiffness in the general population

<p>Abstract</p> <p>Background</p> <p>Cardiovascular diseases (CVD) are the main cause of death and disability in developed countries. In most cases, the progress of CVD is influenced by environmental factors and multifactorial inheritance. The purpose of this study was to investigate the association between <it>APOE </it>genotypes, cardiovascular risk factors, and a non-invasive measure of arterial stiffness in the Brazilian population.</p> <p>Methods</p> <p>A total of 1493 urban Brazilian individuals were randomly selected from the general population of the Vitoria City Metropolitan area. Genetic analysis of the <it>APOE </it>polymorphism was conducted by PCR-RFLP and pulse wave velocity analyzed with a noninvasive automatic device.</p> <p>Results</p> <p>Age, gender, body mass index, triglycerides, creatinine, uric acid, blood glucose, blood pressure phenotypes were no different between ε2, ε3 and ε4 alleles. The ε4 allele was associated with higher total-cholesterol (p < 0.001), LDL-C (p < 0.001), total-cholesterol/HDL-C ratio (p < 0.001), LDL/HDL-C ratio (p < 0.001), lower HDL-C values (p < 0.001) and higher risk to obesity (OR = 1.358, 95% CI = 1.019-1.811) and hyperuricemia (OR = 1.748, 95% CI = 1.170-2.611). Nevertheless, pulse wave velocity (p = 0.66) measures were no different between genotypes. The significant association between APOE genotypes and lipid levels persisted after a 5-year follow-up interval, but no interaction between time and genotype was observed for lipids longitudinal behavior.</p> <p>Conclusion</p> <p>The ε4 allele of the <it>APOE </it>gene is associated with a worse lipid profile in the Brazilian urban population. In our relatively young sample, the observed effect of <it>APOE </it>genotype on lipid levels was not translated into significant effects in arterial wall stiffness.</p

SLCO1B1 rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group

Background\ud Recent studies reported the association between SLCO1B1 polymorphisms and the development of statin-induced myopathy. In the scenario of the Brazilian population, being one of the most heterogeneous in the world, the main aim here was to evaluate SLCO1B1 polymorphisms according to ethnic groups as an initial step for future pharmacogenetic studies.\ud \ud Methods\ud One hundred and eighty-two Amerindians plus 1,032 subjects from the general urban population were included. Genotypes for the SLCO1B1 rs4149056 (c.T521C, p.V174A, exon 5) and SLCO1B1 rs4363657 (g.T89595C, intron 11) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis with the Rotor Gene 6000® instrument.\ud \ud Results\ud The frequencies of the SLCO1B1 rs4149056 and rs4363657 C variant allele were higher in Amerindians (28.3% and 26.1%) and were lower in African descent subjects (5.7% and 10.8%) compared with Mulatto (14.9% and 18.2%) and Caucasian descent (14.8% and 15.4%) ethnic groups (p < 0.001 and p < 0.001, respectively). Linkage disequilibrium analysis show that these variant alleles are in different linkage disequilibrium patterns depending on the ethnic origin.\ud \ud Conclusion\ud Our findings indicate interethnic differences for the SLCO1B1 rs4149056 C risk allele frequency among Brazilians. These data will be useful in the development of effective programs for stratifying individuals regarding adherence, efficacy and choice of statin-type.PCJLS is recipient from fellowship from FAPESP, Proc. 2010-17465-8, Brazil. The technical assistance of the Laboratory of Genetics and Molecular Cardiology group, Heart Institute group is gratefully acknowledged

Genetic factors influencing warfarin dose in Black-African patients: a systematic review and meta-analysis.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high inter-individual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in Black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively while rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in Black Africans to evaluate genetic factors determining warfarin response

Association between UCP2A55V polymorphism and risk of cardiovascular events in patients with multi-vessel coronary arterial disease

BACKGROUND: UCP2 (uncoupling protein 2) plays an important role in cardiovascular diseases and recent studies have suggested that the A55V polymorphism can cause UCP2 dysfunction. The main aim was to investigate the association of A55V polymorphism with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease and preserved left ventricular function. METHODS: The participants of the MASS II were genotyped for the A55V polymorphism using allele-specific PCR assay. Survival curves were calculated with the Kaplan–Meier method and evaluated with the log-rank statistic. The relationship between baseline variables and the composite end-point of cardiac death, acute myocardial infarction (AMI), refractory angina requiring revascularization and cerebrovascular accident were assessed using a Cox proportional hazards survival model. RESULTS: There were no significant differences for baseline variables according genotypes. After 2 years of follow-up, dysglycemic patients harboring the VV genotype had higher occurrence of AMI (p=0.026), Death+AMI (p=0.033), new revascularization intervention (p=0.009) and combined events (p=0.037) as compared with patients carrying other genotypes. This association was not evident in normoglycemic patients. CONCLUSIONS: These findings support the hypothesis that A55V polymorphism is associated with UCP2 functional alterations that increase the risk of cardiovascular events in patients with previous coronary artery disease and dysglycemia

<it>SLCO1B1 </it>rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group

Abstract Background Recent studies reported the association between SLCO1B1 polymorphisms and the development of statin-induced myopathy. In the scenario of the Brazilian population, being one of the most heterogeneous in the world, the main aim here was to evaluate SLCO1B1 polymorphisms according to ethnic groups as an initial step for future pharmacogenetic studies. Methods One hundred and eighty-two Amerindians plus 1,032 subjects from the general urban population were included. Genotypes for the SLCO1B1 rs4149056 (c.T521C, p.V174A, exon 5) and SLCO1B1 rs4363657 (g.T89595C, intron 11) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis with the Rotor Gene 6000® instrument. Results The frequencies of the SLCO1B1 rs4149056 and rs4363657 C variant allele were higher in Amerindians (28.3% and 26.1%) and were lower in African descent subjects (5.7% and 10.8%) compared with Mulatto (14.9% and 18.2%) and Caucasian descent (14.8% and 15.4%) ethnic groups (p Conclusion Our findings indicate interethnic differences for the SLCO1B1 rs4149056 C risk allele frequency among Brazilians. These data will be useful in the development of effective programs for stratifying individuals regarding adherence, efficacy and choice of statin-type.</p