Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study

Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene-environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10-18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p = 0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p < 0.0001), and nevus densities were higher on sun-exposed sites (92 per m(2)) than sun-protected sites (58 per m(2)) (p < 0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95% CI 0.92-0.96) than in DZ pairs (0.61, 95%CI 0.49-0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi.

Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples

This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 kg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 mug/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and CYP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importantly, we show elevated levels of CYP2C9 protein to be associated with cadmium accumulation in liver. No mechanism that explains this association is apparent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an individual's non-workplace exposure to cadmium, or an individual's CYP2C9 genotype may be a risk factor for cadmium accumulation. A positive correlation was found between liver CYP3A4 protein and subject age. Levels of liver CYPIA2 protein, but not other CYP forms, were increased in people more exposed to cigarette smoke, but there was no association between CYPIA2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this sample group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasians. CYP2A6 gene types W/W, WIC, and CIC were not associated with variations in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twenty-five kidney samples tested but was detectable in liver samples of all but two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6(D)) in this sample group to be about 7%, typical of Caucasian populations. (C) 2001 Elsevier Science Inc. All rights reserved.

Genetic and environmental contributions to cannabis dependence in a national young adult twin sample

Background. This paper examines genetic and environmental contributions to risk of cannabis dependence. Method. Symptoms of cannabis dependence and measures of social, family and individual risk factors were assessed in a sample of 6265 young adult male and female Australian twins born 1964-1971. Results. Symptoms of cannabis dependence were common: 11(.)0% of sample (15(.)1% of men and 7(.)8% of women) reported two or more symptoms of dependence. Correlates of cannabis dependence included educational attainment, exposure to parental conflict, sexual abuse, major depression, social anxiety and childhood conduct disorder. However, even after control for the effects of these factors, there was evidence of significant genetic effects on risk of cannabis dependence. Standard genetic modelling indicated that 44(.)7% (95% CI = 15-72(.)2) of the variance in liability to cannabis dependence could be accounted for by genetic factors, 20(.)1% (95 CI = 0-43(.)6) could be attributed to shared environment factors and 35(.)3% (95% CI = 26(.)4-45(.)7) could be attributed to non-shared environmental factors. However, while there was no evidence of significant gender differences in the magnitude of genetic and environmental influences, a model which assumed both genetic and shared environmental influences on risks of cannabis dependence among men and shared environmental but no genetic influences among women provided an equally good fit to the data. Conclusions. There was consistent evidence that genetic risk factors are important determinants of risk of cannabis dependence among men. However, it remains uncertain whether there are genetic influences on liability to cannabis dependence among women.

D2 dopamine receptor gene polymorphism discriminates two kinds of novelty seeking

Cloninger's psychobiological model of personality as applied to substance misuse has received mixed support. Contrary to the model, recent data suggest that a combination of high novelty seeking (NS) and high harm avoidance (HA) represents a significant risk for the development of severe substance misuse. A genetic polymorphism previously implicated in severe substance dependence, the A1 allele of the D2 dopamine receptor (DRD2) gene, was examined in relation to NS and HA amongst 203 adolescent boys. Specifically, we hypothesized that subjects with the A1 + allele (A1/A1 and A1/A2 genotypes) would report stronger NS and would exhibit a more positive relationship between NS and HA than those with the A1-allele (A2/A2 genotypes). These predictions were supported. The correlation between NS and HA in 81 A1 + allelic boys (r = 0.27, P = 0.02), and that in the 122 A1- allelic boys (r = -0.15, P = 0.09), indicated that this relationship differed according to allelic status (F = 8.52, P < 0:004). Among those with the A1-allele, the present results are consistent with the traditional view that novelty seeking provides positive reinforcement, or the fulfillment of appetitive drives. In contrast, novelty seeking in those with the A1 + allele appears to include a negative reinforcement or self-medicating function. (C) 2002 Elsevier Science Ltd. All rights reserved.

Australian empirical study into genetic discrimination

This paper outlines a major empirical study that is being undertaken by an interdisciplinary team into genetic discrimination in Australia. The 3-year study will examine the nature and extent of this newly emerging phenomenon across the perspectives of consumers, third parties, and the legal system and will analyze its social and legal dimensions. Although the project is confined to Australia, it is expected that the outcomes will have significance for the wider research community as this is the most substantial study of its kind to be undertaken to date into genetic discrimination.

Direction of Causation Modeling Between Cross-Sectional Measures of Parenting and Psychological Distress in Female Twins

Under certain conditions, cross-sectional analysis of cross-twin intertrait correlations can provide important information about the direction of causation (DOC) between two variables. A community-based sample of Australian female twins aged 18 to 45 years was mailed an extensive Health and Lifestyle Questionnaire (HLQ) that covered a wide range of personality and behavioral measures. Included were self-report measures of recent psychological distress and perceived childhood environment (PBI). Factor analysis of the PBI yielded three interpretable dimensions: Coldness, Overprotection, and Autonomy. Univariate analysis revealed that parental Overprotection and Autonomy were best explained by additive genetic, shared, and nonshared environmental effects (ACE), whereas the best-fitting model for PBI Coldness and the three measures of psychological distress (Depression, Phobic Anxiety, and Somatic Distress) included only additive genetic and nonshared environmental effects (AE). A common pathway model best explained the covariation between (1) the three PBI dimensions and (2) the three measures of psychological distress. DOC modeling between latent constructs of parenting and psychological distress revealed that a model which specified recollected parental behavior as the cause of psychological distress provided a better fit than a model which specified psychological distress as the cause of recollected parental behavior. Power analyses and limitations of the findings are discussed.

Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls

Context Previous studies have reported that early initiation of cannabis (marijuana) use is a significant risk factor for other drug use and drug-related problems. Objective To examine whether the association between early cannabis use and subsequent progression to use of other drugs and drug abuse/dependence persists after controlling for genetic and shared environmental influences. Design Cross-sectional survey conducted in 1996-2000 among an Australian national volunteer sample of 311 young adult (median age, 30 years) monozygotic and dizygotic same-sex twin pairs discordant for early cannabis use (before age 17 years). Main Outcome Measures Self-reported subsequent nonmedical use of prescription sedatives, hallucinogens, cocaine/other stimulants, and opioids; abuse or dependence on these drugs (including cannabis abuse/dependence); and alcohol dependence. Results Individuals who used cannabis by age 17 years had odds of other drug use, alcohol dependence, and drug abuse/dependence that were 2.1 to 5.2 times higher than those of their co-twin, who did not use cannabis before age 17 years. Controlling for known risk factors (early-onset alcohol or tobacco use, parental conflict/separation, childhood sexual abuse, conduct disorder, major depression, and social anxiety) had only negligible effects on these results. These associations did not differ significantly between monozygotic and dizygotic twins. Conclusions Associations between early cannabis use and later drug use and abuse/dependence cannot solely be explained by common predisposing genetic or shared environmental factors. The association may arise from the effects of the peer and social context within which cannabis is used and obtained. In particular, early access to and use of cannabis may reduce perceived barriers against the use of other illegal drugs and provide access to these drugs.

Estimates of global and regional potential health gains from reducing multiple major risk factors

Background Estimates of the disease burden due to multiple risk factors can show the potential gain from combined preventive measures. But few such investigations have been attempted, and none on a global scale. Our aim was to estimate the potential health benefits from removal of multiple major risk factors. Methods We assessed the burden of disease and injury attributable to the joint effects of 20 selected leading risk factors in 14 epidemiological subregions of the world. We estimated population attributable fractions, defined as the proportional reduction in disease or mortality that would occur if exposure to a risk factor were reduced to an alternative level, from data for risk factor prevalence and hazard size. For every disease, we estimated joint population attributable fractions, for multiple risk factors, by age and sex, from the direct contributions of individual risk factors. To obtain the direct hazards, we reviewed publications and re-analysed cohort data to account for that part of hazard that is mediated through other risks. Results Globally, an estimated 47% of premature deaths and 39% of total disease burden in 2000 resulted from the joint effects of the risk factors considered. These risks caused a substantial proportion of important diseases, including diarrhoea (92%-94%), lower respiratory infections (55-62%), lung cancer (72%), chronic obstructive pulmonary disease (60%), ischaemic heart disease (83-89%), and stroke (70-76%). Removal of these risks would have increased global healthy life expectancy by 9.3 years (17%) ranging from 4.4 years (6%) in the developed countries of the western Pacific to 16.1 years (43%) in parts of sub-Saharan Africa. Interpretation Removal of major risk factors would not only increase healthy life expectancy in every region, but also reduce some of the differences between regions, The potential for disease prevention and health gain from tackling major known risks simultaneously would be substantial.

Risk factors for basal cell carcinoma: a case-control study

A controlled trial was performed with the purpose of investigating which factors could be considered of significant risk for the development of basal cell carcinoma. A total of 259 cases of basal cell carcinoma diagnosed from July 1991 to July 1992 were compared with 518 controls matched for age and sex. All subjects in both groups were white. Protocol data were submitted to statistical analysis by the chi-square test and by multiple conditional logistic regression analysis and the following conclusions were reached: 1) light skin color (types I and II of the Fitzpatrick classification), odds ratio of 2.8; outdoor work under constant sunlight, odds ratio of 5.0; the presence of actinic lesions due to exposure to the sun, odds ratio of 4.9, are risk factors perse. 2) Type III skin in the Fitzpatrick classification only represents a risk factor when the patient reports a history of intense sunburns, but not in the absence of such a history. 3) Sunburns per se do not represent a risk factor althorig the point made in item 2 of these conclusions is valid. 4) Other suspected risk factors whose significance was not confirmed by multiple conditioned logistic regression analysis were: residence in rural areas, light eyes and blond hair color, extent of the awareness of the "sun x skin cancer" relationship, familial occurrence of skin cancer, excessive exposure to the sun, and freckles appearing in childhood.

Environmental exposure to toxicants mixtures from a multi-purpose estuary: perspectives for a biomonitoring study in Portugal

This work was focused on a multi-purpose estuarine environment (river Sado estuary, SW Portugal) around which a number of activities (e.g., fishing, farming, heavy industry, tourism and recreational activities) coexist with urban centres with a total of about 200 000 inhabitants. Based on previous knowledge of the hazardous chemicals within the ecosystem and their potential toxicity to benthic species, this project intended to evaluate the impact of estuarine contaminants on the human and ecosystem health. An integrative methodology based on epidemiological, analytical and biological data and comprising several lines of evidence, namely, human contamination pathways, human health effects, consumption of local produce, estuarine sediments, wells and soils contamination, effects on commercial benthic organisms, and genotoxic potential of sediments, was used. The epidemiological survey confirmed the occurrence of direct and indirect (through food chain) exposure of the local population to estuarine contaminants. Furthermore, the complex mixture of contaminants (e.g., metals, pesticides, polycyclic aromatic hydrocarbons) trapped in the estuary sediments was toxic to human liver cells exposed in vitro, causing cell death, oxidative stress and genotoxic effects that might constitute a risk factor for the development of chronic-degenerative diseases, on the long term. Finally, the integration of data from several endpoints indicated that the estuary is moderately impacted by toxicants that affect also the aquatic biota. Nevertheless, the human health risk can only be correctly assessed through a biomonitoring study including the quantification of contaminants (or metabolites) in biological fluids as well as biomarkers of early biological effects (e.g., biochemical, genetic and omics-based endpoints) and genetic susceptibility in the target population. Data should be supported by a detailed survey to assess the impact of the contaminated seafood and local farm products consumption on human health and, particularly, on metabolic diseases or cancer development.

The role of an illiquidity factor in the Portuguese stock market

This study examines the role of illiquidity (proxied by the proportion of zero returns) as an additional risk factor in asset pricing. We use Portuguese monthly data, covering the period between January 1988 and December 2008. We compute an illiquidity factor using the Fama and French [Fama, E. F., and K. R. French (1993), "Common risk factors in the returns on stocks and bonds", Journal of Financial Economics, Vol. 33, Nº. 1, pp. 3-56] procedure and analyze the performance of CAPM, Fama-French three-factor model and illiquidity-augmented versions of these models in explaining both the time-series and the cross-section of returns. Our results reveal that the effect of characteristic liquidity is subsumed by the models considered, but the risk of illiquidity is not priced in the Portuguese stock market.

Papel do polimorfismo Pro12 Ala no gene PPAR Gama 2 na obesidade e diabetes mellitus tipo 2 - uma meta análise

A obesidade e a diabetes mellitus tipo 2 (DM2) são considerados dois grandes problemas de saúde pública. A má alimentação e a falta de atividade física encontram-se entre os principais desencadeadores de um crescente número de indivíduos obesos, diabéticos e com sensibilidade à insulina diminuída. Este aumento tem motivado a comunidade científica a investigar cada vez mais para o elevado contributo da herança genética associada aos fatores sociais e nutricionais. O gene dos recetores ativados por proliferadores do peroxissoma gama 2 (PPARγ2) desempenha um papel importante no metabolismo lipídico. Uma vez que o PPARγ2 é maioritariamente expresso no tecido adiposo, uma redução moderada da sua atividade tem influência na sensibilidade à insulina, diabetes, e outros parâmetros metabólicos. Vários estudos sugerem que tanto fatores genéticos como fatores ambientais (tais como a dieta), poderão estar envolvidos na formação de padrões associados ao polimorfismo Pro12Ala com a composição corporal em diferentes populações humanas. Os diversos estudos genéticos envolvendo o estudo do polimorfismo Pro12Ala do PPARγ2 na suscetibilidade de possuir risco de diabetes e obesidade em várias populações têm proposto conclusões diversas. Em alguns parece haver mais associações do que outros e, às vezes, não demonstram sequer associação. Desta forma, o presente trabalho teve como objectivo contribuir para a elucidação do impacto do polimorfismo Pro12Ala do PPARγ2 na resistência à insulina associada à DM2 e na obesidade, mediante estudo sistematizado da literatura existente até à data, através de meta análise. Do total de uma pesquisa de 63 publicações, foram incluídos 32 artigos no presente estudo, sendo que destes 25 foram incluídos na síntese qualitativa e 11 incluídos na sintese quantitativa. No presente trabalho pode-se concluir que existe evidência estatística que suporta a hipótese de que o polimorfismo Pro12Ala do PPARγ2 pode ser considerado um fator protetor para a DM2 [p <0,05 e OR (odds ratio) 0,702, com IC (intervalos de confiança) com valores que nunca incluem o 1]. No entanto, e mediante os mesmos pressupostos, o mesmo polimorfismo pode ser considerado um fator de risco ao desenvolvimento de obesidade, pela evidência estatística [p <0,05 e OR de 1,196, com IC com valores que nunca incluem o 1].

Role of malnutrition and parasite infections in the spatial variation in children’s anaemia risk in Northern Angola

Anaemia has a significant impact on child development and mortality and is a severe public health problem in most countries in sub-Saharan Africa. Nutritional and infectious causes of anaemia are geographically variable and anaemia maps based on information on the major aetiologies of anaemia are important for identifying communities most in need and the relative contribution of major causes. We investigated the consistency between ecological and individual-level approaches to anaemia mapping, by building spatial anaemia models for children aged ≤15 years using different modeling approaches. We aimed to a) quantify the role of malnutrition, malaria, Schistosoma haematobium and soil-transmitted helminths (STH) for anaemia endemicity in children aged ≤15 years and b) develop a high resolution predictive risk map of anaemia for the municipality of Dande in Northern Angola. We used parasitological survey data on children aged ≤15 years to build Bayesian geostatistical models of malaria (PfPR≤15), S. haematobium, Ascaris lumbricoides and Trichuris trichiura and predict small-scale spatial variation in these infections. The predictions and their associated uncertainty were used as inputs for a model of anemia prevalence to predict small-scale spatial variation of anaemia. Stunting, PfPR≤15, and S. haematobium infections were significantly associated with anaemia risk. An estimated 12.5%, 15.6%, and 9.8%, of anaemia cases could be averted by treating malnutrition, malaria, S. haematobium, respectively. Spatial clusters of high risk of anaemia (>86%) were identified. Using an individual-level approach to anaemia mapping at a small spatial scale, we found that anaemia in children aged ≤15 years is highly heterogeneous and that malnutrition and parasitic infections are important contributors to the spatial variation in anemia risk. The results presented in this study can help inform the integration of the current provincial malaria control program with ancillary micronutrient supplementation and control of neglected tropical diseases, such as urogenital schistosomiasis and STH infection.

Risk factors for metabolic bone disease in Crohn's disease patients

Background: The aim was to evaluate the presence of metabolic bone disease (MBD) in patients with Crohn’s disease (CD) and to identify potential etiologic factors. Methods: The case–control study included 99 patients with CD and 56 controls with a similar age and gender distribution. Both groups had dual-energy x-ray absorptionmetry and a nutritional evaluation. Single nucleotide polymorphisms at the IL1, TNF-a, LTa, and IL-6 genes were analyzed in patients only. Statistical analysis was performed using SPSS software. Results: The prevalence of MBD was significantly higher in patients (P ¼ 0.006). CD patients with osteoporosis were older (P < 0.005), small bowel involvement and surgical resections were more frequent (P < 0.005), they more often exhibited a penetrating or stricturing phenotype (P < 0.05), duration of disease over 15 years (P < 0.005), and body mass index (BMI) under 18.5 kg/m2 (P < 0.01) were more often found. No association was found with steroid use. Patients with a Z-score < 2.0 more frequently had chronic active disease (P < 0.05). With regard to diet, low vitamin K intake was more frequent (P ¼ 0.03) and intake of total, monounsaturated, and polyunsaturated fat was higher in patients with Z-score < 2.0 (P < 0.05). With respect to genetics, carriage of the polymorphic allele for LTa252 A/G was associated with a higher risk of osteoporosis (P ¼ 0.02). Regression analysis showed that age over 40 years, chronic active disease, and previous colonic resections were independently associated with the risk of developing MBD. Conclusions: The prevalence of MBD was significantly higher in CD patients. Besides the usual risk factors, we observed that factors related to chronic active and long-lasting disease increased the risk of MBD.

Fatty acids, IL6, and TNFα polymorphisms: an example of nutrigenetics in Crohn's disease

Objectives - The aim of this work was to study the interaction between genetic polymorphisms (single-nucleotide polymorphisms, SNPs) of pro- and anti-inflammatory cytokines and fat intake on the risk of developing Crohn's disease (CD) or modifying disease activity. Methods - Seven SNPs in interleukin 1 (IL1), tumor necrosis factor alpha (TNFalpha), lymphotoxin alpha (LTalpha), and IL6 genes were analyzed in 116 controls and 99 patients with CD. The type of fat intake was evaluated, and the interaction between SNPs and dietary fat in modulating disease activity was analyzed. Results - Individuals who were homozygous for the IL6-174G/C polymorphism had a six-fold higher risk for CD (odds ratio (OR)=6.1; 95% confidence interval (95% CI)=1.9-19.4), whereas the TT genotype on the TNFalpha-857C/T polymorphism was associated with more active disease (OR=10.4; 95% CI=1.1-94.1). A high intake of total, saturated, and monounsaturated fats, as well as a higher ratio of n-6/n-3 polyunsaturated fatty acid (PUFA), was associated with a more active phenotype (P<0.05). Furthermore, there was an interaction between dietary fat intake and SNPs, with a high intake of saturated and monounsaturated fats being associated with active disease, mainly in patients carrying the variant alleles of the 857 TNFalpha polymorphism (OR=6.0, 95% CI=1.4-26.2; OR=5.17; 95% CI=1.4-19.2, respectively) and the 174 IL6 polymorphism (OR=2.95; 95% CI=1.0-9.1; OR=3.21; 95% CI=1.0-10.4, respectively). Finally, low intake of n-3 PUFA and high n-6/n-3 PUFA ratio in patients with the TNFalpha 857 polymorphism were associated with higher disease activity (OR=3.6; 95% CI=1.0-13.0; OR=5.92; 95% CI=1.3-26.5, respectively). Conclusions - These results show that different types of fat may interact with cytokine genotype, modulating disease activity.