The genetics of coronary heart disease: the contribution of twin studies

Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.

Two-locus Linkage Analysis Applied to Putative Quantitative Trait Loci for Lipoprotein(a) Levels

Plasma levels of lipoprotein(a) _ Lp(a) _ are associated with cardiovascular risk (Danesh et al., 2000) and were long believed to be influenced by the LPA locus on chromosome 6q27 only. However, a recent report of Broeckel et al. (2002) suggested the presence of a second quantitative trait locus on chromosome 1 influencing Lp(a) levels. Using a two-locus model, we found no evidence for an additional Lp(a) locus on chromosome 1 in a linkage study among 483 dizygotic twin pairs.

ADH genotype does not modify the effects of alcohol on high-density lipoprotein

Background: Alcohol consumption has beneficial effects on mortality which are mainly due to reduction in cardiovascular disease. These are believed to be due, at least in part, to the increase in plasma high-density lipoprotein (HDL) which is associated with alcohol consumption. It has been proposed that ADH3 genotype modifies the relationships between alcohol intake and cardiovascular disease by altering the HDL response to alcohol. The aim of this paper was to test for effects of ADH2 and ADH3 genotypes on the response of HDL components to habitual alcohol consumption. Methods: Adult male and female subjects were genotyped for ADH2 and ADH3; and plasma HDL cholesterol, apolipoprotein A-I, and apolipoprotein A-II were measured. Nine hundred one subjects had both ADH2 and ADH3 genotypes and HDL cholesterol results, while 753 had both genotypes and all three lipid results. The effect of alcohol intake on the three measured HDL components, and a factor score derived from them, was estimated for each of the ADH2 and ADH3 genotype groups. Results: All the measured components of HDL increased with increasing alcohol consumption over the range of intakes studied, 0-4 drinks per day. There were no significant interactions between alcohol consumption and ADH2 or ADH3 genotypes. Conclusions: The concept that alcohol dehydrogenase genotype and alcohol metabolic rate modify the effects of alcohol on plasma HDL concentration is not supported by our results.

Relative importance of female-specific and non-female-specific effects on variation in iron stores between women

Women have lower iron stores than men because of iron loss during their reproductive years. However, variation between women could result from differences in iron loss, aspects of iron homeostasis common to men and women, or a combination of both. We compared the effects of age, menopause, menstrual blood loss and the number of pregnancies (sex-specific factors), and the effects of genetic variation, on markers of iron stores. We assessed how much the same genes or other familial factors influence iron status in both men and women. Data from 2039 female twins who participated in studies of reproductive health and iron status were used to estimate the proportions of variation that could be ascribed to genes, environment and measured factors. Significant effects of age, menopausal status and magnitude of menstrual blood loss were demonstrated, accounting for up to 18% of variance in serum ferritin in this sample, but number of children had no significant effect. Genetic effects were more than twice as great as sex-specific effects. The within-pair similarity of ferritin values in dizygotic female twin pairs was greater than for dizygotic opposite-sex pairs, but this difference was not quite significant, consistent with a minor role for sex-specific factors; and the opposite-sex within-pair differences did not diminish significantly with age. We conclude that the contribution of genetic differences between women to variation in iron stores outweighs the comparatively small effects of interindividual variation in iron loss through variation in menstruation and number of pregnancies.

Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population

The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors multiple genes that have been suggested to play a role in lipid metabolism and previous studies indicated the presence of a quantitative trait locus (QTL) for cholesterol levels in genetic isolates. To establish the relevance of genetic variation at chromosome 19 for plasma levels of lipids and apolipoproteins in the general, out-bred Caucasian population, we performed a linkage study in four independent samples, including adolescent Dutch twins and adult Dutch, Swedish and Australian twins totaling 493 dizygotic twin pairs. The average spacing of short-tandem-repeat markers was 6 - 8 cM. In the three adult twin samples, we found consistent evidence for linkage of chromosome 19 with LDL cholesterol levels ( maximum LOD scores of 4.5, 1.7 and 2.1 in the Dutch, Swedish and Australian sample, respectively); no indication for linkage was observed in the adolescent Dutch twin sample. The QTL effects in the three adult samples were not significantly different and a simultaneous analysis of the samples increased the maximum LOD score to 5.7 at 60 cM pter. Bivariate analyses indicated that the putative LDL-C QTL also contributed to the variance in ApoB levels, consistent with the high genetic correlation between these phenotypes. Our study provides strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL-C plasma levels in outbred Caucasian populations.

Substance-use disorders and psychological distress among police arrestees

Objectives: To determine the 12-month prevalence of substance-use disorders and psychological morbidity in an Australian arrestee population. Design: Cross-sectional descriptive study. Participants and setting: 288 police arrestees at the Brisbane City Police Watch House in February and March 2001. Outcome measures: Prevalence of drug and alcohol disorders; psychological caseness according to the 28-item General Health Questionnaire; demographics and index offences. Results: 86% of the arrestees had at least one substance-use disorder; most had multiple disorders. More than 80% were substance dependent. The predominant substances used were amphetamines, marijuana, opioids and alcohol. 82% of the men and 94% of the women were suffering significant psychological distress. Conclusions: Development of services for detoxification and treatment of this population is a pressing need. The findings provide crucial information for the planning and implementation of drug courts and court diversion systems.

The genetics of alcohol intake and of alcohol dependence

Background: Because alcohol has multiple dose-dependent consequences, it is important to understand the causes of individual variation in the amount of alcohol used. The aims of this study were to assess the long-term repeatability and genetic or environmental causes of variation in alcohol intake and to estimate the degree of overlap with causes of susceptibility to alcohol dependence. Methods: Data were used from three studies conducted between 1980 and 1995 on volunteer adult male and female Australian twin subjects. In each study, alcohol intake was reported both as quantity X frequency and as past-week data. Repeatability was calculated as correlations between occasions and between measures, and the effects of genes and environment were estimated by multivariate model fitting to the twin pair repeated measures of alcohol use. Relationships between mean alcohol use and the lifetime history of DSM-III-R alcohol dependence were tested by bivariate model fitting. Results: Repeatability of the alcohol intake measures was between 0.54 and 0.85, with the highest repeatability between measures within study and the lowest repeatability between the first and last studies. Reported alcohol consumption was mainly affected by genetic factors affecting all times of study and by nonshared environmental factors (including measurement error) unique to each time of study. Genes that affect alcohol intake do affect alcohol dependence, but genetic effects unique to dependence are also significant; environmental effects are largely unique to either intake and dependence. Conclusions: Nearly all the repeatable component of variation in alcohol intake is due to genetic effects. Genes affecting intake also affect dependence risk, but there are other genes that affect dependence alone. Studies aiming to identify genes that affect alcohol use disorders need to test loci and candidate genes against both phenotypes.

Genetic Epidemiology of Alcohol-Induced Blackouts

Background: Alcohol-induced blackouts (ie, periods of anterograde amnesia) have received limited recent research attention. Objective: To examine the genetic epidemiology of lifetime blackouts and having had 3 or more blackouts in a year, including analyses controlling for the frequency of intoxication. Design, Setting, and Participants: Members of the young adult Australian Twin Register, a volunteer twin panel born between January 1, 1964, and December 3 1, 1971, were initially registered with the panel as children by their parents between 1980 and 1982. They underwent structured psychiatric telephone inter-views from February 1996 through September 2000. The current sample contains 2324 monozygotic and dizygotic twin pairs (mean [SDI age 29.9 [2.5] years) for whom both twins' responses were coded for blackout questions and for frequency of intoxication. Main Outcome Measure: Data on lifetime blackouts and having had 3 or more blackouts in a year were collected within an examination of the genetic epidemiology of alcoholism. Results: A lifetime history of blackouts was reported by 39.3% of women and 52.4% of men; 11.4% of women and 20.9% of men reported having had 3 or more blackouts in a year. The heritability of lifetime blackouts was 52.5% and that of having had 3 or more blackouts in a year was 57.8%. Models that controlled for frequency of intoxication found evidence of substantial genetic contribution unique to risk for the blackouts and a significant component of genetic risk shared with frequency of intoxication. Conclusions: The finding of a substantial genetic contribution to liability for alcohol-induced blackouts including a component of genetic loading shared with frequency of intoxication may offer important additional avenues to investigate susceptibility to alcohol-related problems.

Drug use patterns and mental health of regular amphetamine users during a reported 'heroin drought'

Aims The present study extends the findings of a pilot study conducted among regular amphetamine users in Newcastle, NSW, in 1998. It compares key features between current participants in a state capital city (Brisbane) and a regional city (Newcastle) and between the 1998 and current Newcastle sample. Design Cross-sectional survey. Setting Brisbane and Newcastle, Australia. Participants The survey was conducted among 214 regular amphetamine users within the context of a randomized controlled trial of brief interventions for amphetamine use. Measurements Demographic characteristics, past and present alcohol and other drug use and mental health, treatment, amphetamine-related harms and severity of dependence. Findings The main findings were as follows: (i) the rate of mental health problems was high among regular amphetamine users and these problems commonly emerged after commencement of regular amphetamine use; (ii) there were regional differences in drug use with greater accessibility to a wider range of drugs in a state capital city and greater levels of injecting risk-taking behaviour outside the capital city environment; and (iii) there was a significant increase in level of amphetamine use and percentage of alcohol users, a trend for a higher level of amphetamine dependence and a significant reduction in the percentage of people using heroin and benzodiazepines among the 2002 Newcastle cohort compared to the 1998 cohort. Conclusions Further longitudinal research is needed to elucidate transitions from one drug type to another and from recreational to injecting and regular use and the relationship between drug use and mental health in prospective studies among users. Implications Intervention research should evaluate the effectiveness of interventions aimed at: preventing transition to injecting and regular use of amphetamines; toward reducing levels of depression among amphetamine users and interventions among people with severe psychopathology and personality disorders; and toward reducing the prevalence of tobacco dependence among amphetamine users.

Acceptability and feasibility of a community-based screening programme for melanoma in Australia

The evaluation of a community-based screening programme for melanoma (SkinWatch) in 18 regional communities (total adult population >30 years 63 035) in Queensland, Australia is described. The aim of the SkinWatch programme was to promote whole-body skin screening for melanoma by primary care physicians. The programme included community education, education and support for local medical practitioners and open-access skin screening clinics. Programme delivery was achieved through assistance of local volunteers. All programme activities and resources were recorded for process evaluation. A baseline telephone survey (n = 3110) and a telephone survey four months after programme launch (n = 680) assessed community awareness of the SkinWatch programme and, 37 face-to-face interviews with community members, doctors and community leaders were conducted to assess satisfaction with the programme. A sample of 1043 of 16 383 residents who attended the skin screening clinics provided as part of the programme were interviewed to assess reasons for attending, and positive and negative aspects of SkinWatch programme. Community awareness of the SkinWatch programme increased by over 30% (p < 0.001) within four months of the start of the programme. Interview participants described the SkinWatch programme as a useful service for the communities and 90% stated they would revisit the clinics. A total of 43% of all attendees were over 50 years old, and nearly 50% were men. These findings demonstrate the acceptability and feasibility of a community-based screening programme for melanoma in rural areas. Volunteers were instrumental in increasing community ownership of and involvement in the SkinWatch programme.

Genetic effects on alcohol dependence risk: re-evaluating the importance of psychiatric and other heritable risk factors

Background. Genetic influences have been shown to play a major role in determining the risk of alcohol dependence (AD) in both women and men; however, little attention has been directed to identifying the major sources of genetic variation in AD risk. Method. Diagnostic telephone interview data from young adult Australian twin pairs born between 1964 and 1971 were analyzed. Cox regression models were fitted to interview data from a total of 2708 complete twin pairs (690 MZ female, 485 MZ male, 500 DZ female, 384 DZ male, and 649 DZ female/male pairs). Structural equation models were fitted to determine the extent of residual genetic and environmental influences on AD risk while controlling for effects of sociodemographic and psychiatric predictors on risk. Results. Risk of AD was increased in males, in Roman Catholics, in those reporting a history of major depression, social anxiety problems, and conduct disorder, or (in females only) a history of suicide attempt and childhood sexual abuse; but was decreased in those reporting Baptist, Methodist, or Orthodox religion, in those who reported weekly church attendance, and in university-educated males. After allowing for the effects of sociodemographic and psychiatric predictors, 47 % (95 % CI 28-55) of the residual variance in alcoholism risk was attributable to additive genetic effects, 0 % (95 % CI 0-14) to shared environmental factors, and 53 % (95 % CI 45-63) to non-shared environmental influences. Conclusions. Controlling for other risk factors, substantial residual heritability of AD was observed, suggesting that psychiatric and other risk factors play a minor role in the inheritance of AD.

Web-based screening and brief intervention for hazardous drinking: a double-blind randomized controlled trial

Background Strong evidence exists for the efficacy of screening and brief intervention for reducing hazardous drinking. However, problems have been highlighted with respect to its implementation in health-care systems, not least of which is a reluctance of some doctors to discuss alcohol proactively with their patients. Aims To determine the efficacy of a novel web-based screening and brief intervention (e-SBI) to reduce hazardous drinking. Design A double-blind randomized controlled trial. Setting A university student health service. Participants A total of 16 7 students (17-26 years) were recruited in the reception area and completed a 3-minute web-based screen including the Alcohol Use Disorder Identifiation Test (AUDIT) questionnaire. Of these, 112 tested positive, and 104 (52 females) who consented to follow-up were included in the trial. Measurements Drinking frequency, typical occasion quantity, total volume, heavy episode frequency (females > 80 g ethanol, males > 120 g ethanol), number of personal problems, an academic problems score. Intervention Participants were randomized to 10-15 minutes of web-based assessment and personalized feedback on their drinking (intervention, n = 5 1) or to a leaflet-only control group (n = 5 3). Findings Mean baseline AUDIT scores for control and intervention groups were 16.6 (SD = 6.0) and 16.6 (SD = 5.7). At 6 weeks, participants receiving e-SBI reported significantly lower total consumption (geometric mean ratio = 0.74; 9 5 % confidence interval: 0.56-0.96), lower heavy episode frequency (0.63; 0.42-0.92) and fewer personal problems (0.70; 0.54-0.91). At 6 months personal problems remained lower (0.76; 0.60-0.97), although consumption did not differ significantly. At 6 months, academic problems were lower in the intervention group relative to controls (0.72; 0.51-1.02). Conclusions e-SBI reduced hazardous drinking among university students, to an extent similar to that found for practitioner-delivered brief interventions in the general population. e-SBI offers promise as a strategy to reduce alcohol-related harm in a way that is non-intrusive, appealing to the target group, and capable of being incorporated into primary care. Research is required to replicate the findings, to determine the duration of intervention effects, and to investigate the mechanisms by which the intervention operates.

The role of drinking restraint in alcohol dependence: validation of the temptation and restraint inventory in an alcohol dependent sample

Objective: The Temptation and Restraint Inventory (TRI) is commonly used to measure drinking restraint in relation to problem drinking behavior. However, as yet the TRI has not been validated in a clinical group with alcohol dependence. Method: Male (n = 111) and female (n = 57) inpatients with DSM-IV diagnosed alcohol dependence completed the TRI and measures of problem drinking severity, including the Alcohol Dependence Scale and the quantity, frequency and week total of alcohol consumed. Results: The factor structure of the TRI was replicated in the alcohol dependent sample. Cognitive Emotional Preoccupation (CEP), one of the two higher order factors of the TRI, demonstrated sound predictive power toward all dependence severity indices. The other higher order factor, Cognitive Behavioral Control (CBC), was related to frequency of drinking. There was limited support for the CEP/CBC interactional model of drinking restraint. Conclusions: Although the construct validity of the TRI was sound, the measure appears more useful in understanding the development, maintenance and severity of alcohol-related problems in nondependent drinkers. The TRI may show promise in detecting either continuous drinking or heavy episodic type dependent drinkers.