RESUMO
Animal studies have suggested that angiopoietin-like 4 (Angptl4) regulates adiposity through central and peripheral mechanisms. The aim of this study was to investigate whether serum concentration and adipose tissue expression of Angptl4 are associated with obesity-related parameters in humans. Altogether, 75 dizygotic (DZ) and 46 monozygotic (MZ) twin pairs were studied, from the FinnTwin12 and FinnTwin16 cohorts. Among the MZ pairs, 21 were discordant for body mass index (BMI) (intra-pair BMI-difference >2.5 kg/m², age 23-33 years). Serum Angptl4 (s-Angptl4) levels were measured by ELISA, and adipose tissue gene expression was analyzed by genome-wide transcript profiling. In MZ twin pairs discordant for BMI, s-Angptl4 and adipose tissue ANGPTL4 mRNA (at-ANGPTL4) levels were significantly decreased (P = 0.04 and P = 0.03, respectively) in obese twins as compared with their nonobese cotwins. In all twins, intra-pair differences in s-Angptl4 levels were inversely correlated with intra-pair differences in BMI (r = -0.27, P = 0.003). In individual MZ twins, at-ANGPTL4 expression was inversely correlated with BMI (r = -0.44, P = 0.001) and positively correlated with at-LIPE (r = 0.24, P = 0.01) and at-ABHD5 (r = 0.41, P = 0.005) expression. Our results demonstrated that variation in Angptl4 concentration was only modestly accounted for by genetic factors and suggest a role for Angptl4 in acquired obesity in humans.
Assuntos
Tecido Adiposo/metabolismo , Angiopoietinas/metabolismo , Proteínas Sanguíneas/metabolismo , Obesidade , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismo , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/genética , Biópsia , Glicemia/análise , Proteínas Sanguíneas/genética , Composição Corporal , Índice de Massa Corporal , Feminino , Finlândia , Expressão Gênica , Humanos , Estudos Longitudinais , Masculino , Obesidade/sangue , Obesidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/análise , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genéticaRESUMO
Proton magnetic resonance spectroscopy ((1)H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that (1)H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Esquizofrenia/metabolismo , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismo , Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Glicerilfosforilcolina/metabolismo , Hipocampo/metabolismo , Humanos , Inositol/metabolismo , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Fosfocreatina/metabolismo , Fosforilcolina/metabolismo , Córtex Pré-Frontal/metabolismo , Prótons , Esquizofrenia/diagnóstico , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/psicologiaRESUMO
BACKGROUND: The aim of this study was to investigate the possible correlation between smoking status and biomarkers of exposure (BoE) and biological effect (BoBE) in monozygotic twins discordant for smoking status (smoker and non-smoker pairs). By eliminating potential genetic variability in this manner, a clearer pattern of the effects of lifestyle and environmental exposures should become apparent. METHODS: This was a cross-sectional study on monozygotic healthy twins (44 subjects, 26 males and 18 females) with a mean age 31.5 years. BoE to cigarette smoke and BoBE were measured in body fluids (24 h urine and blood) after medical pre-screening. RESULTS: All BoE were significantly higher in the smoker twins. Among BoBE, 11-dehydrothromboxane B(2) (11-dehydro TBX), 2,3-dinorthromboxane B(2) (2,3-dinor TBX), 8-epi-prostaglandin F2α (8-epiPGF), hydroxyproline (OH-P), fibrinogen, white blood cell (WBC), neutrophil and lymphocyte counts and heart rate were statistically significantly increased in the smoker compared to the non-smoker twins. Moreover, statistically significant correlations between neutrophil count and 11-dehydro TBX (r=0.32), WBC and 8-epiPGF (r=0.33), OH-P and 8-epiPGF (r=0.49) and heart rate and fibrinogen (r=0.46) were observed. CONCLUSIONS: The study results confirmed the reliability of the BoE for the evaluation of smoking status. Moreover, a subset of the BoBE, reported as being associated with inflammatory conditions and early stages of vascular disorders, has emerged as showing a consistent relationship with smoking status from the present and the previous studies. By using monozygotic twin pairs, genetic variability has been excluded as a possible source of variability in this study. These results should assist in the interpretation of other population studies using these biomarkers.
Assuntos
Fumar/metabolismo , Gêmeos Monozigóticos/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Estudos Transversais , Exposição Ambiental , Feminino , Humanos , Masculino , Fatores de Risco , Fumar/sangue , Fumar/genética , Fumar/urina , Gêmeos Monozigóticos/genéticaRESUMO
Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.
Assuntos
Analgésicos Opioides/farmacocinética , Farmacogenética/métodos , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/metabolismo , Adulto , Alfentanil/efeitos adversos , Alfentanil/farmacocinética , Alfentanil/farmacologia , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Dor/genética , Dor/metabolismo , Medição da Dor , Percepção da Dor , Adulto JovemRESUMO
The relative influence of genetics and the environment on factors associated with cardiovascular disease (CVD) and metabolic syndrome (MetS) remains unclear. We performed model-fitting analyses to quantify genetic, common environmental, and unique environmental variance components of factors associated with CVD and MetS [waist circumference, blood pressure, fasting plasma glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and fasting plasma lipids] in adult male and female monozygotic twins reared apart or together. We also investigated whether MetS components share common influences. Plasma cholesterol and triglyceride concentrations were highly heritable (56-77%, statistically significant). Waist circumference, plasma glucose and insulin, HOMA-IR, and blood pressure were moderately heritable (43-57%, statistically significant). Unique environmental factors contributed to the variance of all variables (20-38%, perforce statistically significant). Common environmental factors contributed 23, 30, and 42% (statistically significant) of the variance of waist circumference, systolic blood pressure, and plasma glucose, respectively. Two shared factors influenced MetS components; one influenced all components except HDL cholesterol, another influenced only lipid (triglyceride and HDL cholesterol) concentrations. These results suggest that genetic variance has a dominant influence on total variance of factors associated with CVD and MetS and support the proposal of one or more underlying pathologies of MetS.
Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Meio Ambiente , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Adolescente , Adulto , Idoso , Análise de Variância , Doenças Cardiovasculares/metabolismo , Estudos Transversais , Metabolismo Energético , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Fatores de Risco , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/metabolismo , Adulto JovemRESUMO
Individuals differ widely in cortisol output over the day and cortisol reactivity to challenge, both of which are relevant to disease risk. There is limited evidence concerning the heritability of these differences, so we evaluated the heritability of cortisol levels in the afternoon and cortisol reactivity using a twin design. The study involved 80 monozygotic (MZ) and 70 dizygotic (DZ) same-sex twin pairs aged 11.2 years on average. Salivary cortisol was measured in the afternoon at home before and after playing a computer game. Ratings of excitement and upset were also obtained, and objective task performance was assessed. Salivary cortisol levels averaged 4.08 (S.D. 2.3) nmol/l at pretask baseline, and declined on average over the session to 3.45 (1.9) nmol/l immediately after the tasks and 2.87 (1.6) nmol/l 10min later. There were, however, marked individual differences, with cortisol reactivity (difference between pretask baseline and post-task 1) ranging from +4.53 to -6.23nmol/l. Intra-class correlations for all the cortisol parameters were substantially greater for MZ (range 0.41-0.57) than for DZ (0.11-0.29) twin pairs. Quantitative genetic modelling confirmed significant heritability for pretask baseline cortisol (58%), the two post-task values (60 and 56%), and cortisol reactivity (44%). The study lacked power for assessing sex differences. Subjective reports of excitement were also somewhat heritable, but there was little covariation of cortisol and subjective responses, so genetic influences on covariation could not be tested. These findings indicate that individual differences in children's cortisol levels recorded before tasks and cortisol reactivity to behavioural challenges are influenced by genetic factors.
Assuntos
Hidrocortisona/metabolismo , Característica Quantitativa Herdável , Saliva/metabolismo , Criança , Ritmo Circadiano , Estudos de Coortes , Feminino , Humanos , Individualidade , Masculino , Agitação Psicomotora , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismoRESUMO
Nicotine and its primary oxidative metabolites are metabolized in part by glucuronidation. Genetic variation in UGT isoenzymes that catalyze glucuronidation activity suggests that variation in glucuronidation rate is in part genetically determined. The relative contribution of genetic and environmental sources to individual differences in the rate of glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine was estimated in a twin study of nicotine pharmacokinetics. Glucuronidation rate was defined using measures that either accounted for variability in renal clearance or assumed the same relative renal clearance of parent drug and glucuronide conjugate across individuals. The former definition resulted in highly correlated nicotine and cotinine glucuronidation measures that were substantially influenced by the combined effect of additive (heritable) and non-additive (dominant and epistatic) genetic effects. These findings suggest that genetic variation in UGT isoenzymes that act in additive and interactive ways is an important determinant of individual variability in nicotine and cotinine metabolism via glucuronidation pathways.
Assuntos
Glucuronosiltransferase/genética , Nicotina/farmacocinética , Adulto , Cotinina/metabolismo , Feminino , Frequência do Gene , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nicotina/metabolismo , Gêmeos/metabolismo , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismoRESUMO
Neuroticism is widely used as an explanatory concept in etiological research of psychopathology. To clarify what neuroticism actually represents, we investigated the phenotypic and genetic relationship between neuroticism and the morning cortisol secretion. In the current classic twin study, 125 female twin pairs (74 monozygotic and 51 dizygotic pairs) participated. For each participant, 4 different neuroticism scores were available to calculate a neuroticism composite score that was used in the statistical analyses. The morning cortisol secretion was assessed by 4 salivary samples in the 1st hour after awakening. Significant genetic influences for the neuroticism composite score (55%), and each of the 4 cortisol samples (52%-69%) were found. There was no phenotypic or genotypic relationship between neuroticism and morning cortisol secretion. Although neuroticism and cortisol were both heritable traits, they did not share any genetic influences.
Assuntos
Hidrocortisona/análise , Transtornos Neuróticos/metabolismo , Saliva/química , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismo , Adulto , Biomarcadores/análise , Ritmo Circadiano/genética , Feminino , Humanos , Modelos Genéticos , Análise Multivariada , Transtornos Neuróticos/genética , Gêmeos , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
UNLABELLED: Low adiponectin levels have been associated with high body mass index, low insulin sensitivity, and diabetes. OBJECTIVE: To assess the relationships between changes in serum adiponectin concentration and adiposity, glucose, and insulin in response to long-term overfeeding in identical twins and to calculate the twin resemblance in serum adiponectin concentrations. SUBJECTS AND DESIGN: Twenty-four sedentary young men [mean (+/-SD) age, 21+/-2 yr] who constituted 12 pairs of healthy identical twins were studied for metabolic and adiponectin changes in response to overfeeding. INTERVENTION: Subjects were overfed by 84,000 kcal over a 100-day period. OUTCOME MEASURES: The overfeeding study provides an opportunity to examine the relationships between adiponectin and changes in body weight, adiposity, plasma glucose and insulin. RESULTS: Serum adiponectin concentration correlated positively with body weight (r= 0.41, p=0.05) at baseline but not with indicators of adiposity or with visceral fat. No relationship existed between baseline adiponectin concentration and body weight or adiposity gains with overfeeding. However, serum adiponectin decreased significantly by -2.35+/-0.48 microg/ml (p=0.001) in response to overfeeding. Baseline adiponectin levels correlated negatively with changes in plasma fasting glucose levels (r=-0.53, p=0.01) and homeostasis model assessment index (r=-0.41, p=0.05), independently of fat mass. The intrapair coefficient for twin resemblance (r=0.75, p=0.001) strongly suggests that baseline serum adiponectin concentration is a familial trait. CONCLUSIONS: These data provide evidence that adiponectin concentration is a familial trait in normal-weight individuals, that it decreases when challenged by positive energy balance, and that its overfeeding-induced variations are correlated with glucose and insulin levels.
Assuntos
Insulina/metabolismo , Hipernutrição/metabolismo , Gêmeos Monozigóticos , Adiponectina/sangue , Adulto , Glicemia/metabolismo , Humanos , Insulina/sangue , Resistência à Insulina , Leptina/sangue , Masculino , Hipernutrição/sangue , Gêmeos Monozigóticos/sangue , Gêmeos Monozigóticos/metabolismoRESUMO
One's ultimate phenotype is the result of a combination of genotype and environment, and includes a poorly understood component termed "developmental noise". This "developmental noise", also known as "intangible variation", is rarely discussed even though it appears to make a significant contribution to the variance of quantitative traits within a species. The molecular basis of developmental noise remains unknown, but it appears to be established in embryonic development and to be retained for the life of the organism. We propose that the molecular basis of developmental noise is, at least in some instances, the epigenetic state of the genome. The stochastic nature of the establishment of epigenetic state, combined with its heritability during mitosis, provides all of the essential components for developmental noise.
Assuntos
Cor de Cabelo/genética , Cabelo/metabolismo , Animais , Diferenciação Celular/fisiologia , Epigênese Genética/fisiologia , Cor de Cabelo/fisiologia , Camundongos , Transcrição Gênica/fisiologia , Estudos em Gêmeos como Assunto , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/metabolismoRESUMO
Modest genetic effects on morning, but not late-day, cortisol levels have been established. Environmental demands may influence basal cortisol levels later in the day. Thus, we anticipated that individuals in the same family would have similar afternoon cortisol levels to the extent that they share aspects of their environment. We examined afternoon basal cortisol levels measured across 3 consecutive days in mothers and fathers and in multiple offspring in two separate large and longitudinal studies. Study I involved 321 families with singletons while study II involved 233 families with twins. Modest family similarity was apparent for afternoon basal cortisol levels in both studies. Spouses' cortisol levels were also correlated. Data from study II demonstrated that family resemblance in afternoon cortisol was accounted for by underlying shared environmental factors, but not underlying genetic factors. Shared environment accounted for 62% of the variation in twin afternoon basal cortisol levels and 14% of the variation in parent afternoon basal cortisol levels. We used pooled data from the two studies to examine whether parental depression, socioeconomic status (SES), and offspring sex and age impacted cortisol levels. Female offspring had higher cortisol levels than males, and cortisol decreased with age until about 9 years of age, after which cortisol increased with age. Family similarity persisted after accounting for parental depression, SES, time of day, and offspring sex and age, which suggests that the shared family environment influences parent and offspring stress hormone levels throughout the childhood years.
Assuntos
Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Depressão/metabolismo , Meio Ambiente , Hidrocortisona/metabolismo , Adulto , Fatores Etários , Criança , Pré-Escolar , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Linhagem , Valores de Referência , Saliva/metabolismo , Fatores Sexuais , Estatística como Assunto , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismoRESUMO
The aim of this study was to estimate the heritability of variation in testosterone levels in 12-year-old children, and to explore the overlap in genetic and environmental influences on circulating testosterone levels and androgen-dependent pubertal development. Midday salivary testosterone samples were collected on 2 consecutive days in a sample of 183 unselected twin pairs. Androgen-induced pubertal development was assessed using self-report Tanner scales of pubic hair development (boys and girls) and genital development (boys). A significant contribution of genetic effects to the variance in testosterone levels was found. Heritability was approximately 50% in both boys and girls. The remaining proportion of the variance in testosterone levels could be explained by nonshared environmental influences. The relatively high correlation between testosterone levels of opposite-sex dizygotic twins suggests that sex differences in genes influencing variation in testosterone levels have not yet developed in pre- and early puberty. Variance in pubertal development was explained by a large genetic component, moderate shared environmental influences, and a small nonshared environmental effect. Testosterone levels correlated moderately (r = .31) with pubertal development; the covariance between testosterone levels and pubertal development was entirely accounted for by genetic influences.
Assuntos
Variação Genética , Puberdade/genética , Testolactona , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Puberdade/metabolismo , Saliva/metabolismo , Testolactona/análise , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismoRESUMO
BACKGROUND: Individuals vary greatly in their lipoprotein responses to low-fat diets, with some of this variation being attributable to genes. OBJECTIVE: The purpose was to test the extent to which individual lipoprotein responses to diet can be attributed to genes in the presence of divergent exercise levels. DESIGN: Twenty-eight pairs of male monozygotic twins (one twin mostly sedentary, the other running an average of 50 km/wk more than the sedentary twin) went from a 6-wk 40%-fat diet to a 6-wk 20%-fat diet in a crossover design. The diets reduced fat primarily by reducing saturated and polyunsaturated fat (both from 14% to 4%) while increasing carbohydrate intake from 45% to 65%. RESULTS: Despite the twins' differences in physical activity, the dietary manipulation produced significantly correlated changes (P < 0.05) in the twins' total cholesterol (r = 0.56); LDL cholesterol (r = 0.70); large, buoyant LDL [Svedberg flotation rate (S(f)) 7-12; r = 0.52]; apolipoprotein A-I (r = 0.49); lipoprotein(a) (r = 0.49); electrophoresis measurements of LDL-I (LDLs between 26 and 28.5 nm in diameter; r = 0.48), LDL-IIB (25.2-24.6 nm; r = 0.54), and LDL-IV (22-24.1 nm; r = 0.50); and body weight (r = 0.41). Replacing fats with carbohydrates significantly decreased the size and ultracentrifuge flotation rate of the major LDL and the LDL mass concentrations of large, buoyant LDL; LDL-I; HDL cholesterol; and apolipoprotein A-I and significantly increased concentrations of LDL-IIIA (24.7-25.5 nm) and lipoprotein(a). CONCLUSIONS: Even in the presence of extreme differences in exercise, genes significantly affect changes in LDL, apolipoprotein A-I, lipoprotein(a), and body weight when dietary fats are replaced with carbohydrates.
Assuntos
Colesterol/sangue , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Exercício Físico , Lipoproteínas/sangue , Gêmeos Monozigóticos/metabolismo , Peso Corporal/efeitos dos fármacos , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Humanos , MasculinoRESUMO
Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.
Assuntos
Cromossomos Humanos X/metabolismo , Metilação de DNA , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Cirrose Hepática Biliar/metabolismo , Gêmeos Monozigóticos/metabolismo , Inativação do Cromossomo X , Canais de Cloreto/biossíntese , Canais de Cloreto/genética , Cromossomos Humanos X/genética , Estudos de Coortes , Ilhas de CpG/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Cirrose Hepática Biliar/genética , Linfócitos/metabolismo , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/biossíntese , Peptidilprolil Isomerase/genética , Polimorfismo Genético , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transcrição Gênica/genética , Gêmeos Monozigóticos/genéticaRESUMO
The expression and function of the drug transporter P-glycoprotein are highly variable. Environmental and genetic factors contribute to this variation. We studied the disposition of digoxin, a frequently used probe drug for P-glycoprotein function in humans, in monozygotic (MZ) twins and found that digoxin pharmacokinetics after oral and intravenous administration are highly correlated within MZ twins, supporting the hypothesis of a robust contribution from genetic variance. Our study suggests that studies involving twins could be more widely applied to elucidate pharmacogenetics.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Digoxina/administração & dosagem , Digoxina/farmacocinética , Variação Genética , Gêmeos Monozigóticos/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Adulto , Deutério , Feminino , Genótipo , Humanos , Infusões Intravenosas , Masculino , Fenótipo , Projetos Piloto , Sistema de Registros , Gêmeos Monozigóticos/metabolismo , Adulto JovemRESUMO
BACKGROUND: Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. METHOD: In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. RESULTS: Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. CONCLUSION: Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Predisposição Genética para Doença , Hidrocortisona/metabolismo , Transtornos do Humor/genética , Polimorfismo Genético , Adulto , Alelos , Fator Neurotrófico Derivado do Encéfalo/sangue , Feminino , Genótipo , Humanos , Acontecimentos que Mudam a Vida , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/metabolismo , Saliva/metabolismo , Gêmeos Dizigóticos/metabolismo , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/metabolismo , Gêmeos Monozigóticos/psicologiaRESUMO
Nicotine and its proximate metabolite cotinine are eliminated in part by renal clearance. These compounds are filtered, secreted, and reabsorbed, and the resultant renal clearances are quite variable among individuals and are highly influenced by urine pH. In this study of 139 pairs of twins, we have estimated the genetic and environmental contributions to total renal clearance and net secretory/reabsorptive clearance of nicotine and cotinine. At uncontrolled urine pH both nicotine and cotinine undergo net reabsorption. Additive genetic factors were not important contributors to the variation in total renal clearance of nicotine but played a relatively more substantial role in accounting for the variation in total renal clearance of cotinine (43% of variance). Variations in glomerular filtration rate and the net secretory/reabsorptive clearance of nicotine and cotinine were largely influenced by nonadditive genetic influences (41.5-61% of variance). Earlier research has shown that renal secretory clearance of drugs can be highly heritable, presumably related to genetic variation in transporters. Our study suggests that the renal clearance of drugs that undergo extensive renal reabsorption can be substantially influenced by nonadditive genetic and/or shared environmental factors.
Assuntos
Cotinina/farmacocinética , Taxa de Filtração Glomerular/genética , Rim/metabolismo , Nicotina/farmacocinética , Fumar/genética , Fumar/metabolismo , Gêmeos/genética , Gêmeos/metabolismo , Adulto , Transporte Biológico Ativo/genética , Cotinina/metabolismo , Feminino , Variação Genética , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nicotina/metabolismo , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/metabolismoRESUMO
OBJECTIVE: To test the hypothesis that cervical shortening in polyhydramnios reflects the degree of excess amniotic fluid, and increases with normalisation of amniotic fluid volume. STUDY DESIGN: Prospective cohort study of 40 women with monochorionic twins undergoing interventional procedures between 16-26 weeks. Cervical length was assessed via transvaginal sonography pre-procedure, 1 and 24 hours post-procedure, and results compared between amnioreduction and control procedures. Amniotic fluid index (AFI) was measured pre- and post-procedure. RESULTS: Pre-procedural cervical length correlated with AFI (linear fit = 5.07 -0.04x, R(2) = 0.17, P = 0.03) in patients with polyhydramnios (n = 28). Drainage of 2000 ml fluid (range 700-3500 ml), reduced AFI from 42 cm to 21 cm (P<0.001). Their pre-procedural cervical length did not change at one (mean Delta:-0.1cm, 95%CI, -0.4 to 0.2) or 24 hours (0.2 cm, -0.1 to 0.6) after amnioreduction. There was no change in cervical length at control procedures. CONCLUSION: Cervical shortening in twins with polyhydramnios does not appear to be an acute process; cervical length can be measured before or after therapeutic procedures.
Assuntos
Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , Doenças em Gêmeos/diagnóstico por imagem , Poli-Hidrâmnios/diagnóstico por imagem , Adulto , Estudos de Coortes , Doenças em Gêmeos/patologia , Doenças em Gêmeos/terapia , Feminino , Idade Gestacional , Humanos , Poli-Hidrâmnios/patologia , Poli-Hidrâmnios/terapia , Gravidez , Gêmeos Monozigóticos/metabolismo , Ultrassonografia Pré-NatalRESUMO
OBJECTIVE: To assess if amniotic fluid alpha-fetoprotein (AFAFP) could be useful to determine if both sacs are sampled during an amniocentesis for twin pregnancies. METHOD: We reviewed all amniocenteses performed on twin pregnancies over a 5-year period. Inclusion criteria were restricted to pregnancies where both karyotypes and AFAFP were available on each fetus. Pregnancies complicated by fetal anomalies were excluded. The following information was obtained: maternal age, gestational age at the procedure, karyotypes, AFAFP values, pregnancy and neonatal outcome. Placental pathology reports were used to confirm chorionicity. Analysis was performed to evaluate the impact of the fetal gender and chorionicity on the AFAFP values. RESULTS: 260 pregnancies were reviewed. Mean maternal age was 36.9 years (33.6, 40.1). Gestational age at the time of the procedure was 16.2 weeks (14.5, 17.9). Complications included 1.8% of misdiagnosis (discrepancy between karyotype and gender). The difference of AFAFP values between the two fetuses was statistically larger in dichorionic pregnancies than in monochorionic gestations. Fetal gender had no influence on the AFAFP. CONCLUSION: Amniocentesis in twin pregnancies is associated with a 1.8% risk of misdiagnosis. AFAFP can help to assess the chorionicity of a twin pregnancy. When the difference between the two values is <0.2 MoM and the chorionicity was thought to be dichorionic and the two karyotypes are similar, then failure to sample both sacs should be suspected.
Assuntos
Amniocentese/métodos , Gravidez Múltipla/metabolismo , Gêmeos Dizigóticos/metabolismo , Gêmeos Monozigóticos/metabolismo , alfa-Fetoproteínas/análise , Líquido Amniótico/química , Feminino , Humanos , Recém-Nascido , Cariotipagem , Masculino , GravidezRESUMO
OBJECTIVES: CYP2A6 is the major enzyme involved in nicotine metabolism, yet large interindividual variations in the rate of nicotine metabolism exist within groups of individuals having the same CYP2A6 genotype. We investigated the influence of genetic variation in another potential nicotine-metabolizing enzyme, CYP2B6, and its interaction with CYP2A6, on the metabolism of nicotine. METHODS: Two hundred and twelve healthy Caucasian adult twin volunteers underwent an intravenous infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, for characterization of pharmacokinetic and metabolism phenotypes. Five CYP2B6 genetic polymorphisms causing amino acid substitutions (R22C, Q172 H, S259R, K262R, and R487C) were analyzed. RESULTS: We observed that the CYP2B6*6 haplotype (defined as having both Q172 H and K262R variants) was associated with faster nicotine and cotinine clearance, and that such associations were more prominent among individuals having decreased-activity CYP2A6 genotypes. Statistically significant interactions between CYP2B6 and CYP2A6 genotypes were observed (P<0.003 for nicotine clearance and P<0.002 for cotinine clearance). CONCLUSIONS: Our results indicate that CYP2B6 genetic variation is associated with the metabolism of nicotine and cotinine among individuals with decreased CYP2A6 activity. Further investigation of the roles of CYP2B6 and the interaction between CYP2B6 and CYP2A6 genotypes in mediating nicotine dependence and tobacco-related diseases is merited.