Butyrylcholinesterase Genetic Variants: Association with Cocaine Dependence and Related Phenotypes

Objective: the search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE) metabolizes cocaine, and genetic variants of the BChE gene (BCHE) alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictive behaviors due to differences in effective plasma concentrations of cocaine. Those polymorphisms might also influence users to prefer one of the two main preparations (crack or powder cocaine), despite having equal access to both. the present work investigates polymorphisms in BCHE and if those genetic variants constitute risk factors for cocaine dependence and for crack cocaine use.Methods: A total of 1,436 individuals (698 cocaine-dependent patients and 738 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in BCHE: rs1803274, rs4263329, and rs4680662.Results: for rs4263329, a nominal difference was found between cases and controls. for rs1803274 (the functional SNP), a statistically significant difference was found between patients who used crack cocaine exclusively and those who used only powder cocaine (P = 0.027; OR = 4.36; 95% CI = 1.18-16.04). Allele frequencies and genotypes related to other markers did not differ between cases and controls or between the two cocaine subgroups.Conclusions: Our findings suggest that the AA genotype of rs1803274 is a risk factor for crack cocaine use, which is more addictive than powder cocaine use. Further studies are needed in order to confirm this preliminary result and clarify the role of BCHE and its variants in cocaine dependence.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Sch Med, Dept & Inst Psychiat LIM 23, São Paulo, BrazilUniv São Paulo, Sch Med, Lab Genet & Mol Cardiol LIM 13, Heart Inst InCor, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Clin Neurosci Lab, São Paulo, BrazilUniv São Paulo, Sch Publ Hlth, São Paulo, BrazilUniversidade Federal de São Paulo, Natl Inst Alcohol & Drug Policies, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Clin Neurosci Lab, São Paulo, BrazilUniversidade Federal de São Paulo, Natl Inst Alcohol & Drug Policies, São Paulo, BrazilCNPq: 141762/2008-0Web of Scienc

Amerindian (but not African or European) ancestry is significantly associated with diurnal preference within an admixed Brazilian population

Significant questions remain unanswered regarding the genetic versus environmental contributions to racial/ethnic differences in sleep and circadian rhythms. We addressed this question by investigating the association between diurnal preference, using the morningness–eveningness questionnaire (MEQ), and genetic ancestry within the Baependi Heart Study cohort, a highly admixed Brazilian population based in a rural town. Analysis was performed using measures of ancestry, using the Admixture program, and MEQ from 1,453 individuals. We found an association between the degree of Amerindian (but not European of African) ancestry and morningness, equating to 0.16 units for each additional percent of Amerindian ancestry, after adjustment for age, sex, education, and residential zone. To our knowledge, this is the first published report identifying an association between genetic ancestry and MEQ, and above all, the first one based on ancestral contributions within individuals living in the same community. This previously unknown ancestral dimension of diurnal preference suggests a stratification between racial/ethnic groups in an as yet unknown number of genetic polymorphisms

Association of self-reported ethnicity and genetic ancestry with cardiovascular risk factors in a Brazilian population sample: ELSA - Brazil

Doenças cardiovasculares (DCVs) são a principal causa de morbidade e mortalidade no mundo e a etnia do indivíduo tem uma importante influência no diagnóstico e tratamento dessas doenças. No entanto, as bases das disparidades étnicas ainda não estão completamente esclarecidas. O estudo de uma população com alta miscigenação genética, fornece potenciais maneiras de compreender a influência genética na determinação de fenótipos de doenças complexas, como as cardiovasculares, em raízes ancestrais comuns. O presente estudo teve como objetivo principal associar etnia auto referida e ancestralidade genética em indivíduos de uma coorte brasileira com fatores de risco para doenças cardiovasculares. Identificamos associação entre etnia auto referida e hipertensão arterial, acidente vascular cerebral (AVC) e hipercolesterolemia. Analisando a hipercolesterolemia com mais detalhes, encontramos associação de etnia com níveis séricos de triglicerídeos (TG), lipoproteína de alta densidade (HDL-c) e índice TG/HDL-c. Essas associações foram fortemente dependentes de confundidores socioeconômicos, mas variações existem na força e direção de cada padrão. No entanto, observamos que o efeito de etnia persistiu mesmo após todas as correções. Em seguida derivamos um painel de marcadores para inferir ancestralidade genética continental, para os componentes ancestrais africano, europeu e ameríndio, e determinamos as proporções de ancestralidade na nossa população de estudo. Na sequência, conduzimos análises de associação entre ancestralidade genética e níveis séricos de lipídios, a fim de estudarmos uma variável menos influenciada por fatores socioeconômicos. Nessas análises encontramos associação entre a ancestralidade ameríndia e níveis séricos de HDL-c. Entender porque essa heterogeneidade existe pode prover importantes pistas sobre as razões para uma importante parte das disparidades étnicas em doenças cardiovascularesCardiovascular diseases (CVDs) are the main cause of morbidity and mortality in the world and ethnicity plays an important influence on diagnosis and treatment of these diseases. However, the basis of these ethnic disparities are not fully understood. Studying a population with a high genetic admixture allows potential ways to understand the genetic influence on determination of complex disease phenotypes, such as cardiovascular, in common ancestral roots. The present study had as main aim associating self-reported ethnicity and genetic ancestry in individuals from a Brazilian cohort which have risk factors for cardiovascular diseases. We identified association between self-reported ethnicity and arterial hypertension, stroke, and hypercholesterolemia. Analyzing hypercholesterolemia more deeply, we found association of ethnicity with serum levels of triglycerides (TG), high density lipoprotein cholesterol (HDL-c), and TG/HDL-c index. These associations were strongly dependent on socioeconomic confounders, but there are variations in the strength and direction of each pattern. However, we observed that the ethnicity effect persisted even after all adjustments. Following, we derived a panel of markers to infer continental genetic ancestry for African, European and Amerindian ancestral components, and we have determined the ancestral proportions of ancestry in our study population. After that, we conducted association analysis between genetic ancestry and lipids serum levels, in order to study a variable which is less influenced by socioeconomic factors. In these analyzes we found association between Amerindian ancestry and serum levels of HDL-c. Understanding why there is this heterogeneity can provide important clues about the reason for an important part of ethnic disparities in cardiovascular disease

Smoking and Female Sex: Independent Predictors of Human Vascular Smooth Muscle Cells Stiffening.

AimsRecent evidence shows the rigidity of vascular smooth muscle cells (VSMC) contributes to vascular mechanics. Arterial rigidity is an independent cardiovascular risk factor whose associated modifications in VSMC viscoelasticity have never been investigated. This study's objective was to evaluate if the arterial rigidity risk factors aging, African ancestry, female sex, smoking and diabetes mellitus are associated with VMSC stiffening in an experimental model using a human derived vascular smooth muscle primary cell line repository.MethodsEighty patients subjected to coronary artery bypass surgery were enrolled. VSMCs were extracted from internal thoracic artery fragments and mechanically evaluated using Optical Magnetic Twisting Cytometry assay. The obtained mechanical variables were correlated with the clinical variables: age, gender, African ancestry, smoking and diabetes mellitus.ResultsThe mechanical variables Gr, G'r and G"r had a normal distribution, demonstrating an inter-individual variability of VSMC viscoelasticity, which has never been reported before. Female sex and smoking were independently associated with VSMC stiffening: Gr (apparent cell stiffness) p = 0.022 and p = 0.018, R2 0.164; G'r (elastic modulus) p = 0.019 and p = 0.009, R2 0.184 and G"r (dissipative modulus) p = 0.011 and p = 0.66, R2 0.141.ConclusionFemale sex and smoking are independent predictors of VSMC stiffening. This pro-rigidity effect represents an important element for understanding the vascular rigidity observed in post-menopausal females and smokers, as well as a potential therapeutic target to be explored in the future. There is a significant inter-individual variation of VSMC viscoelasticity, which is slightly modulated by clinical variables and probably relies on molecular factors

Characteristics of cocaine-dependent patients and control subjects.

<p>SD, standard deviation.</p

Genotype frequencies of three BCHE markers in cocaine-dependent patients, by preferred form of cocaine administration.

a<p>rs1803274 AA genotype, P = 0.027; OR = 4.36 (95% confidence interval = 1.18–16.04), between crack users and powder users.</p

Genotype and allele frequencies of three BCHE markers in cocaine-dependent patients and controls.

<p>SNP, single nucleotide polymorphism; HWE, Hardy-Weinberg equilibrium.</p>a<p>rs4263329 GG genotype, P = 0.052, odds ratio = 2.3 (95% confidence interval = 0.99–5.32).</p

Population Structure Analysis.

<p>Graphic representation of the first two principal components for cases and controls genotyped with 64 AIMs, each point in this plot is an individual. The distribution of individuals in the axes is similar for both groups therefore the EIGENSTRAT software was not able to detect a difference in population stratification between cases and controls.</p

Comparison of VSMC mechanics between men and women / ever smokers and non-smokers.

<p>(A) Graph outlining the statistical comparison between men and women regarding VSMC mechanics. Women presented a significant higher apparent VSMC stiffness (Gr) in comparison to men, mainly due to its elastic modulus (G’r). (B) Similarly to what was observed with women, ever smokers presented a significant higher apparent VSMC stiffness (Gr) in comparison to non-smokers, mainly due to its elastic modulus (G’r). Error bars represent 95% CI and their size is compatible with other OMTC experiments in which a per-well analysis was performed. For each patient, 6 replicates of OMTC experiment were performed.</p