The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches.

The recent completion of a rough draft of the human genome sequence has ushered in a new era of molecular genetics research into the inherited basis of a number of complex diseases such as cancer. At the same time, recent twin studies have suggested a limited role of genetic susceptibility to many neoplasms. A reappraisal of family and twin studies for many cancer sites suggests the following general conclusions: (a) all cancers are familial to approximately the same degree, with only a few exceptions (both high and low); (b) early age of diagnosis is generally associated with increased familiality; (c) familiality does not decrease with decreasing prevalence of the tumor-in fact, the trend is toward increasing familiality with decreasing prevalence; (d) a multifactorial (polygenic) threshold model fits the twin data for most cancers less well than single gene or genetic heterogeneity-type models; (e) recessive inheritance is less likely generally than dominant or additive models; (f) heritability decreases for rarer tumors only in the context of the polygenic model but not in the context of single-locus or heterogeneity models; (g) although the family and twin data do not account for gene-environment interactions or confounding, they are still consistent with genes contributing high attributable risks for most cancer sites. These results support continued search for genetic and environmental factors in cancer susceptibility for all tumor types. Suggestions are given for optimal study designs depending on the underlying architecture of genetic predisposition.     

Musiktherapie bei chronischen Kopfschmerzen

PROBLEM: This paper presents a new approach to music therapeutic treatments. We developed a short time treatment ( 8 group sessions) for patients suffering from chronic headaches. The multimodal concept of this headache treatment and particularly the effect of a sound trance on headache patients are explained and evaluated in this paper. METHODS: An evaluation study was done with 34 patients, who belonged to four therapy groups. In order to evaluate this treatment the patients were interviewed and had to fill out several self-rating scales about pain and some psychological variables (e. g. depression) before, directly after and 6-12 months after the treatment. This treatment group (n=26) was compared to a small waiting group (n=9). A case study elucidated the psycho-social anamnesis, and the process and outcome of the music therapy. RESULTS: The case study shows that the sound trance caused a loss of the affect control or at least reduced it. This experience enabled the patients to develop creative solutions, which resulted in a pain relief 6-12 month later. The comparison of the statistic means directly before and after the treatment did not reveal many therapeutic effects. Yet, 6-12 months later many patients reported less days at which they suffered from headaches; and they also significantly improved their ability of pain control. CONCLUSION: The results indicate that music therapy groups are more successful than a waiting group. The study's results agree with numerous other psychological evaluation studies and shows once more that music therapists working with patients suffering from chronic headaches are able to achieve successful results particularly long-dated. Thus, creative therapeutic approaches supplement the medical treatment, as they help the patients to develop an adaptive way of coping their pain. Yet, it will need further research to confirm the benefit of music therapy for patients suffering from chronic pain.     

Relations of genetic and environmental factors in the etiology of epilepsy

We assessed the relations of genetic and environmental factors in the etiology of epilepsy. The study population comprised 9,705 first-degree relatives of 1,951 adults with epilepsy ascertained from voluntary organizations. We calculated standardized morbidity ratios for specific etiologies of epilepsy in the relatives of probands with the same etiologies, using population incidence rates from Rochester, MN, as the reference. Relatives of probands with idiopathic/cryptogenic epilepsy had increased risk for idiopathic/cryptogenic epilepsy and for epilepsy associated with neurological deficit presumed present at birth (cerebral palsy or mental retardation) but not for symptomatic epilepsy associated with postnatal central nervous system insults. Relatives of probands with neurodeficits had increased risks for idiopathic/ cryptogenic epilepsy. Risk for epilepsy was not increased among relatives of probands with postnatal symptomatic epilepsy. The degree of increased risk of idiopathic/cryptogenic epilepsy in relatives of probands with idiopathiclcryptogenic epilepsy diminished with increasing age of the relatives; risk was not increased at age 35 or older. These findings support the possibility of a shared genetic susceptibility to epilepsy and cerebral palsy, and suggest that the genetic contributions to postnatal symptomatic epilepsy are minimal.     

No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism.

OBJECTIVE.--We attempted to replicate a positive allelic association between the A1 allele of DRD2 (the D2 dopamine receptor locus) and alcoholism that has been reported. DESIGN.--We compared allele frequencies at the previously described Taq I restriction fragment length polymorphism system of DRD2 in alcoholics and random population controls. SUBJECTS.--The alcoholic subjects were 44 unrelated white individuals, diagnosed by direct structured interview to have alcohol dependence (by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria). The subjects in our random population control group (N = 68) were also white. RESULTS.--For the control group, allele frequencies at DRD2 were 0.20 (A1) and 0.80 (A2). For the alcoholic group overall, allele frequencies were 0.23 (A1) and 0.77 (A2). There were no significant differences in allele frequencies at the DRD2 locus between alcoholics and controls. The allele frequencies in both groups agreed closely with those observed in most previously described control populations. Subtyping the alcoholic group according to presence or absence of family history of alcoholism, presence or absence of antisocial personality disorder, age of onset, presence or absence of physical withdrawal symptoms, or recent alcohol consumption (as a measure of severity) did not in any case reveal significant differences in allele frequencies. CONCLUSION.--We were not able to replicate the results previously reported. We conclude that our data do not support an allelic association between the A1 allele at DRD2 and alcoholism.     

White matter hyperintensity signals in psychiatric and nonpsychiatric subjects.

OBJECTIVE: As part of an ongoing study investigating the relationship between brain morphology/function and neuropsychological performance in psychopathology, the authors conducted brain magnetic resonance imaging (MRI) studies to investigate the prevalence and psychiatric significance of white matter hyperintensity signals. METHOD: Brain MRI acquisition was done with 0.5 and 1.5 Tesla Philips scanners. Psychiatric subjects (N = 229) and normal volunteers (N = 154) were recruited by newspaper and local advertising and by physician referral. DSM-III-R criteria were used. White matter hyperintensity signals were rated on a 4-point scale of severity. Prevalence rates and risk ratios were calculated. RESULTS: Prevalence rates of hyperintensity signals in all psychiatric subjects (mean age = 34 years, SD = 9) and normal volunteers (mean age = 34, SD = 10) were 6.6% and 9.1%, respectively (a nonsignificant difference). When all psychiatric subjects, subjects under age 45, and subjects age 45 and over in a diagnostic category were considered, there were no statistically significant differences between them and normal volunteers in the same age groups in prevalence of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, and obsessive-compulsive disorder. A significant difference existed between the severity of deep white matter hyperintensity signals in subjects with major depression and normal volunteers. Older age was correlated as a risk factor for white matter hyperintensity signals for psychiatric subjects. CONCLUSIONS: These results do not support previous findings of greater prevalence of hyperintensity signals in bipolar disorder. Significantly higher prevalence rates of hyperintensity signals were seen in subjects with major depression only when severity of the deep white matter hyperintensity signals was considered. Older age is an indirect risk factor for the presence of white matter hypertensity signals, probably as a result of vascular changes associated with concurrent medical illnesses.     

Myeloperoxidase G-463A polymorphism and lung cancer: a HuGE genetic susceptibility to environmental carcinogens pooled analysis.

Myeloperoxidase is a phase I metabolic enzyme that converts the metabolites of benzo[a]pyrene from tobacco smoke into highly reactive epoxides. A polymorphism in the promoter region of myeloperoxidase (463G-->A) has been found to be inversely associated with lung cancer; differences in the association with age and gender have been suggested. We conducted a pooled analysis of individual data from 10 studies (3688 cases and 3874 controls) from the Genetic Susceptibility to Environmental Carcinogens database. The odds ratio for lung cancer was 0.88 (95% confidence interval: 0.80-0.97) for the AG variant of myeloperoxidase G-463A polymorphism, and 0.71 (95% confidence interval: 0.57-0.88) for the AA variant after adjusting for smoking, age, gender, and ethnicity. The inverse association between lung cancer and myeloperoxidase G-463A polymorphism was equally found in males and females (odds ratio for the AA genotype 0.73 [95% confidence interval: 0.56-0.96] and 0.67 [95% confidence interval: 0.46-0.98], respectively), without differences in the association according to age in the two genders. The myeloperoxidase G-463A polymorphism was significantly protective in "ever" smokers but not in "never" smokers. Myeloperoxidase is a key enzyme in tobacco-induced carcinogenesis.     

A genome-wide scan in forty large pedigrees with multiple sclerosis

The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, χ ² = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD > 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS.     

Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study

Summary. Background: Recent studies indicate that arterial cardiovascular diseases and venous thromboembolism (VTE) share common risk factors. A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI. Objectives: The purpose of the present study was to determine the impact of cardiovascular risk factors, including family history of MI, on the incidence of VTE in a prospective, population‐based study. Patients and methods: Traditional cardiovascular risk factors and family history of MI were registered in 21 330 subjects, aged 25–96 years, enrolled in the Tromsø study in 1994–95. First‐lifetime VTE events during follow‐up were registered up to 1 September 2007. Results: There were 327 VTE events (1.40 per 1000 person‐years), 138 (42%) unprovoked, during a mean of 10.9 years of follow‐up. In age‐ and gender‐adjusted analysis, age [hazard ratio (HR) per decade, 1.97; 95% confidence interval (CI), 1.82–2.12], gender (men vs. women; HR, 1.25; 95% CI, 1.01–1.55), body mass index (BMI; HR per 3 kg m^?2, 1.21; 95% CI, 1.13–1.31), and family history of MI (HR, 1.31; 95% CI, 1.04–1.65) were significantly associated with VTE. Family history of MI remained a significant risk factor for total VTE (HR, 1.27; 95% CI, 1.01–1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03–2.07) in multivariable analysis. Blood pressure, total cholesterol, HDL‐cholesterol, triglycerides, and smoking were not independently associated with total VTE. Conclusions: Family history of MI is a risk factor for both MI and VTE, and provides further evidence of a link between venous and arterial thrombosis.     

The continuum of HIV care in Catalonia

The objective was to produce a cascade of care for Catalonia to gain a public health perspective on the overall quality of HIV services and allow comparison with other countries. It was constructed using the Integrated Epidemiological Surveillance System of HIV in Catalonia and data from the PISCIS Cohort. Estimates of the number of people living with HIV in Catalonia are modelled using Spectrum Projection Package 2011 (UNAIDS/WHO). Totals for each stage in the cascade are obtained by applying to the preceding stage a proportion estimated from available surveillance and cohort data. Undiagnosed HIV was estimated from the European literature. The proportions retained in care, on ART and virally suppressed were derived from the PISCIS cohort. Programmatic data on ART consumption was used to validate estimates. By the end of 2011 there were about 33,000 people living with HIV in Catalonia, 71% of which had been both diagnosed and linked to care. We estimate that 61% of all HIV infected persons were retained in care, 56% were on ART and 48% were virally suppressed. These figures data are comparable, although slightly lower, than that of France or the UK. The Cascade of HIV Care in Catalonia is similar to other western European countries such as France and the UK. Direct estimates of the undiagnosed HIV population and linkage to care are desirable but the contribution of cohort data to the cascade highlights their continued importance in HIV surveillance and design of evidence-based health strategies.