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There is considerable evidence that there may be a genetic component contributing to the development of Alzheimer's disease (AD). Some investigators hypothesize that the disease may be related to a genetic defect located on chromosome 21. There is also some reason to suspect that Alzheimer's disease and Parkinson's disease may have some etiologic factors in common. Certainly, many patients with Parkinson's disease develop dementia. Furthermore, some patients with Alzheimer's disease develop extrapyramidal signs such as involuntary muscle movements; these patients seem to have a different prognosis than other Alzheimer's patients. To accurately evaluate the familial relationships of Alzheimer's disease and Parkinson's disease, the family histories of 198 patients with clinically diagnosed Alzheimer's disease were compared with the family histories of 198 age- and sex-matched healthy control subjects. In order to avoid introducing bias into the comparison, Alzheimer's patients with signs of Parkinsonism were excluded from the study. The results indicate that first-degree relatives of an Alzheimer's patient have over three times the relative risk of developing Alzheimer's than do individuals with no first-degree relatives with the disorder. (For purposes of this study, first-degree relative means brother, sister, or parent, since no children of patients in this study have yet developed Alzheimer's disease.) For individuals with two or more first-degree relatives with Alzheimer's disease, the relative risk increases to 40 times that of the control subjects. In keeping with the results of other reports, the familial association is stronger when the age of onset of AD is younger. The relative risk of an individual with a relative developing AD younger than 65 years of age is 7.8, in contrast to a relative risk of 3.3 for those with relatives developing AD at 65 or over. Curiously, there was a strong sex effect in the relationship between AD and Parkinson's disease. Men with relatives with Parkinson's had a relative risk of developing AD of 8.0, while for women, relatives with Parkinson's raised the relative risk to only 1.8. The results suggest not only a strong genetic component to Alzheimer's disease, but also that Alzheimer's disease and Parkinson's disease may have important etiologic features in common. (Consumer Summary produced by Reliance Medical Information, Inc.)

Mutations in the DJ-1 gene lead to autosomal recessive early-onset parkinsonism. We performed F-DOPA and FDG PET neuroimaging in two parkinsonism patients homozygous for DJ-1 mutations, three relatives heterozygous for a DJ-1 mutation and one non-carrier, all from the originally described kindred from The Netherlands. Their characteristics were compared to those of typical Parkinson’s disease patients and healthy controls. Both parkinsonism patients had reduced F-DOPA uptake concordant with typical Parkinson’s disease. In the, clinically unaffected, heterozygous relatives, F-DOPA metabolism was unremarkable, thus not suggesting a dosage effect of the DJ-1 gene. [ABSTRACT FROM AUTHOR]

Introduction: Studies on the role of the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin converting enzyme (ACE) in atherosclerosis have been inconsistent. In a meta-analysis, we recently showed that this relationship is stronger in high risk populations. In this paper, we used a combined functional and population based approach to investigate the gene-environment interaction of the ACE I/D polymorphism in relation to carotid artery wall thickness. Methods: The study was part of the Rotterdam Study, a prospective population based cohort study. In 5321 subjects, IMT was measured in the carotid arteries by ultrasonography and ACE genotype was determined by size analysis of polymerase chain reaction products. Results: In multiple regression analysis, I/D polymorphism and smoking were the main determinants for plasma ACE activity (r²=0.28). There was a positive association between the D allele of the I/D polymorphism and carotid artery thickness among current smokers (p = 0.03). Subjects carrying only one of the risk factors (smoking or the D allele) did not show significant differences in IMT compared with the non-/former smokers group carrying two II alleles, while carriers of both risk factors had significant higher IMT. The association was not present in non-/former smokers. Discussion: The results provide further evidence that genetic and environmental factors interact in the formation of the arterial lesions. This study shows that large population based studies can be extremely helpful in unravelling the genetic origin of complex diseases such as atherosclerosis. [ABSTRACT FROM AUTHOR]

Summary For quantitative traits with a genetic component, random effects approaches are used to test for linkage at observed marker loci. We propose to use these approaches also for binary outcomes observed in sib pairs derived from a population-based cohort study. In addition to a random effect modelling correlation due to polygenic effect, a random effect is included to model the correlation between siblings due to sharing alleles identical by descent (IBD) at the observed marker locus. A two-step analysis is proposed. Firstly, score statistics are computed to test whether correlation is present in the data. Secondly, random effects models are fitted, yielding heritability estimates. To illustrate the methods, data on the contribution of the COL2A1 gene to various binary and quantitative outcomes including the presence of Heberden's nodes and bone mineral density (BMD) are analysed. For most of the traits studied, the score statistics were significant, indicating the presence of genetic effects. For BMD and for Heberden's nodes, the variance explained by the marker locus was 44% (P = 0.0008) and 15% (P = 0.38) respectively. We conclude that the score statistics can be used as a preliminary data analysis. In more sophisticated analysis, heritabilities can be estimated by fitting random effects models. [ABSTRACT FROM AUTHOR]

Presents the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia. Exclusion of the known Alzheimer's disease genes and mutations in the prion protein gene and exons 9-13 of the microtubule; Resemblance of the phenotype to frontotemporal dementia.

Background: Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy. Genetic and iatrogenic forms have been recognised but most are sporadic and of unknown cause. We have studied risk factors for CJD as part of the 1993-95 European Union collaborative studies of CJD in Europe.Methods: The 405 patients with definite or probable CJD who took part in our study had taken part in population-based studies done between 1993 and 1995 in Belgium, France, Germany, Italy, the Netherlands, and the UK. Data on putative risk factors from these patients were compared with data from 405 controls.Findings: We found evidence for familial aggregation of CJD with dementia due to causes other than CJD (relative risk [RR] 2.26, 95% CI 1.31-3.90). No significant increased risk of CJD in relation to a history of surgery and blood transfusion was shown. There was no evidence for an association between the risk of CJD and the consumption of beef, veal, lamb, cheese, or milk. No association was found with occupational exposure to animals or leather. The few positive findings of the study include increased risk in relation to consumption of raw meat (RR 1.63 [95% CI 1.18-2.23]) and brain (1.68 [1.18-2.39]), frequent exposure to leather products (1.94 [1.13-3.33]), and exposure to fertiliser consisting of hoofs and horns (2.32 [1.38-2.91]). Additional analyses, for example stratification by country and of exposures pre-1985 and post-1985, suggest that these results should be interpreted with great caution.Interpretation: Within the limits of the retrospective design of the study, our findings suggest that genetic factors other than the known CJD mutations may play an important part in CJD. Iatrogenic transmission of disease seems rare in this large population-based sample of patients with CJD. There is little evidence for an association between the risk of CJD and either animal exposure, or consumption of processed bovine meat or milk products for the period studied. [ABSTRACT FROM AUTHOR]

Objective: A genetic association study was performed to investigate whether radiographical osteoarthritis (ROA) was associated with specific genotypes of the insulin-like growth factor I (IGF-1) gene.Methods: Subjects aged 55-65 years were selected from a population-based study of which ROA at the knee, hip, spine, and hand was assessed. Genotypes were determined of a polymorphism in the promoter region of the IGF-1 gene.Results: The IGF-1 locus was significantly associated with the presence of ROA (over-all adjusted OR for heterozygous subjects = 1.9, 95% CI 1.2, 3.1 and for homozygous subjects 3.6, 95% CI 0.8, 16.2).Conclusion: These results suggest that variation at the IGF-1 locus is associated with ROA development and may play a part in ROA pathogenesis. To confirm these findings replication in another population-based sample is needed. [ABSTRACT FROM AUTHOR]

Analyzes whether genes involved in the dopaminergic and serotonergic systems can influence temperament dimensions. Dopamine transporter genes; Dimensions of novelty seeking and harm avoidance; Genetic polymorphism.

Abstract: IGF-I is an important growth factor for the mammary gland. We evaluated the relationship of the IGF-I CA n polymorphism with breast cancer risk in Caucasian postmenopausal women and performed a meta-analysis of published data. The IGF-I CA n polymorphism was genotyped in 4091 from the Rotterdam Study. A disease-free survival analysis was performed along with a meta-analysis of all available data on IGF-I CA n polymorphism and breast cancer risk. During follow-up 159 women were diagnosed with breast cancer. The disease-free survival analysis adjusted for age at entry, age at menopause, body mass index and waist hip ratio yielded a HR=0.97 (95% CI=0.59–1.58) for CA19 non-carriers against carriers. The meta-analysis using the random-effects model gave a pooled OR of 1.26 (95% CI=0.95–1.82) for IGF-I CA19 non-carriers versus CA19 homozygous carriers. According to these results, the IGF-I CA19 promoter polymorphism is not likely to predict the risk of breast cancer. [Copyright &y& Elsevier]

Abstract: TGF-β1 has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-β1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR=1.4; 95% confidence interval (CI)=1.1–2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR=1.4, 95% CI=1.1–2.0) against non-carriers. Our data suggest that the TGF-β1 Leu10Pro polymorphism might play a role in breast cancer risk. [Copyright &y& Elsevier]

Abstract: To test the hypothesis that infectious exposures may be involved in glioma aetiology, we have analysed space–time clustering and seasonal variation using population-based data from the South of the Netherlands between 1983 and 2001. Knox tests for space–time interactions between cases were applied, with spatial coordinates of the addresses at time of diagnosis, and with distance to the Nth nearest neighbour. Data were also analysed by a second order procedure based on K-functions. Tests for heterogeneity and Edwards’ test for sinusoidal variation were applied to examine seasonal variation of incidence. There was statistically significant space–time clustering in the Eastern, but not in the Western part of the region. Clustering was only present in adults, particularly in less densely populated areas. There was no evidence for seasonal variation. The results support a role for infectious exposures in glioma aetiology that may act preferentially in certain geographical areas. [Copyright &y& Elsevier]

Examines the association of cigarette smoking with dementia and Alzheimer's disease, and whether this relation depended on age, sex, and the apolipoprotein E genotype (APOE). Methods of selecting participants; Findings including risk for individuals without the APOEepsilon4 allele; Interpretation that smoking is associated with a doubling of the risk of dementia and Alzheimer's disease.

Abstract: Iron is a reactive oxygen species and has been implicated in the pathogenesis of Alzheimer''s disease (AD). In a population-based cohort study, including 268 incident AD patients and 2079 control individuals, we investigated the influence of the HFE C282Y and H63D variants and the apolipoprotein E4 (APOEɛ4) allele on the incidence, and age at onset of AD. There was no significant difference in the frequency of HFE variants in AD patients compared to controls. There was no significant effect modification by the APOEɛ4 allele. The mean age at onset was earlier in H63D homozygotes compared to non-carriers of this variant, in men (76.9±3.2 compared to 82.2±1.7) and women (82.1±3.9 compared to 84.5±1.7). In addition, in APOEɛ4 carriers, the mean age at onset of AD was earlier in men homozygous for the H63D variant (73.2±2.1 versus 78.7±1.6, p =0.05). Our results suggest that HFE variants are not strong determinants of AD in the general population but may modify the age of onset. [Copyright &y& Elsevier]