HLA antigens and acute rheumatic fever: evidence for a recessive susceptibility gene linked to HLA

From 60 probands with acute rheumatic fever (ARF), 19 multiplex families segregating for ARF were ascertained. The parents and rheumatic and normal sibs of the probands in these 19 families were also studied. HLA typing using the microlymphocytotoxic assay was then performed on the 60 unrelated probands, the multiplex families, and 234 unrelated controls using 23 antigens from the HLA-A and -B loci. The controls lacked a past history of ARF and were from the same geographic locality. Calculations of relative risk demonstrate an increase of HLA-B5 antigen in the 60 patients, but the result might not be significant from the point of view of multiple comparisons. Nevertheless, affected sib pairs from the multiplex families show 93% concordance for both or one HLA haplotype. A formal linkage analysis demonstrates that a recessive etiology is most likely (lod score of 3.3) with approximately 68% of cases being due to a gene closely linked to HLA and in linkage disequilibrium with HLA-B5. The remaining 32% of cases are due to other familial factors such as polygenic inheritance or common environmental factors. The results confirm a strong genetic predisposition to ARF and its heterogeneous nature in families.     

Genetic analysis of Alzheimer's disease: A summary of contributions to GAW8

Participants in the Alzheimer's disease component of GAW8 had access to three collections of pedigrees, complete with marker data from chromosomes 19 and 21. There were a total of 94 independent pedigrees and more than 2,000 individuals. Onset of the disorder varied widely among pedigrees. These data are briefly summarized along with a discussion of the problems associated with performing genetic analyses of Alzheimer's disease. The majority of the workshop participants performed an analysis either with some of the data contributed to the workshop or with data simulated on pedigrees of the same structure and disease status as were contributed. There were also a few purely methodological contributions. The contributions are summarized in three general areas: family association and phenotype, linkage analysis, and heterogeneity tests. © 1993 Wiley-Liss, Inc.     

A study of three techniques for time-space clustering in hodgkin's disease

Three techniques for disease time-space clustering analysis, those of Knox, Mantel and Ederer-Myers-Mantel, were applied to simulated data so as to study their sensitivities. The simulated data corresponded to three alternative non-null models for the distribution, transmission and development of Hodgkin's disease (HD) which were formulated in accordance with the results of published studies. The results indicate that the three techniques may not be sufficiently sensitive to the clustering in a real data set of HD cases. Therefore, the inconclusive results obtained to date with regard to clustering of HD may be related to the low power of the statistical techniques employed.     

Linkage of Alzheimer's disease to chromosome 21 and chromosome 19 markers: Effect of age of onset assumptions

Age of onset heterogeneity in Alzheimer's disease families was modelled by allowing for different liability classes for affected individuals according to their age of onset when calculating lod scores to chromosome 21 and chromosome 19 markers. Linkage to chromosome 21 was supported in the Boston data set, and the method of age correction did not greatly change the lod scores when only affected individuals were analyzed. The location of a gene on chromosome 19 for late age of onset illness was affected by the assumptions about early onset individuals. © 1993 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Susceptibility genes for familial Alzheimer's disease on chromosomes 19 and 21: A reality check

Linkage data from 92 FAD kindreds were analyzed by lod score analysis under various assumptions of disease penetrance, marker allele frequencies, and heterogeneity. Multilocus linkage analysis supports the existence of a gene in 40%–65% of families with predominantly late-onset illness (after age 65) on chromosome 19 between D19S13 and ATP1A3. Evidence for a second FAD gene on chromosome 21 is weaker and stems primarily from a few families with early-onset disease. Our findings also indicate that choice of the genetic model for FAD and marker allele frequencies may be crucial to conclusions about linkage and heterogeneity. © 1993 Wiley-Liss, Inc.     

Analysis of discrete phenotypes using a multipoint identity-by-descent method: Application to Alzheimer's disease

The multipoint identity-by-descent method was developed to detect linkage to a specific chromosomal region through partitioning the genetic variance. This method has previously been applied to quantitative traits, and here is extended to a qualitative trait, where a dichotomous affected/unaffected status variable is transformed to a quantitative variable by incorporating covariates. This method is applied to the Alzheimer's disease data sets from Genetic Analysis Workshop 8, to investigate putative linkage to chromosomes 19 and 21. The multipoint identity-by-descent method is used to test for linkage through the qualitative trait, and for excess sharing of the chromosomal region among affected sibs. Results are compared to those of the affected-pedigree-member method and classical linkage analysis. None of these methods gave results showing clear linkage, with the only marginally significant results occurring for the Boston data set on chromosome 19 and the Duke data set for chromosome 21 using the multipoint identity-by-descent method. © 1993 Wiley-Liss, Inc.     

The weighted rank pairwise correlation statistic for linkage analysis: Simulation study and application to Alzheimer's disease

The weighted rank pairwise correlation (WRPC) statistic has been proposed as a robust test of genetic linkage, particularly adapted to the analysis of large and complex pedigrees and for age-dependent and heterogeneous diseases. In this paper a simulation study is presented. Validity and power of the WRPC test are studied and compared to the Haseman-Elston sibpair method for various types of problems. The power of the WRPC test is slightly lower than the Haseman-Elston method for analyzing a large number of small randomly chosen pedigrees. It is higher however in presence of genetic heterogeneity or for analyzing large individual pedigrees. Recently, evidence of linkage of Alzheimer's disease with a locus on chromosome 14, D14s43, has been obtained by the Lod-score method. We reanalyze these data using the WRPC test, essentially confirming the results of the Lod-score method. The WRPC test statistic is higher than the equivalent Lod-score statistic for the two pedigrees which show strong evidence of linkage with the two methods. The global WRPC test statistic is slightly lower than the Lod-score test statistic. The WRPC test, however, makes no hypothesis of a specific genetic transmission model and can be computed very quickly; in addition, an exact P-value can be computed by simulation for individual pedigrees. © 1994 Wiley-Liss, Inc.     

Genetic heterogeneity in Alzheimer's disease: A grade of membership analysis

Grade of membership analysis (GoM) may have particular relevance for genetic epidemiology. The method can flexibly relate genetic markers, clinical features, and environmental exposures to possible subtypes of disease termed pure types even when population allele frequencies and penetrance functions are not known. Hence, GoM may complement existing strategies that sometimes fail in the presence of heterogeneity or when case definition is not well established. To illustrate the method, individuals in the Seattle data set were evaluated with respect to affection status, age at onset, pedigree, sex, and genetic markers on chromosomes 19 and 21. Seven pure types were found which we have designated as: Early Onset, Late Onset, Probable, and Unaffected 1 to Unaffected 4. © 1993 Wiley-Liss, Inc.     

The impact of some parameters on linkage analysis of Alzheimer's disease

The two-point lod score linkage analysis of familial Alzheimer's disease is sensitive to the parameters of age-dependent penetrance rate, phenocopy rate, heterogeneity, and marker gene frequency. If unsuitable parameters are used, it may lead to false negative evidence against linkage. However, it is clear that, in some cases, it may lead to false positive evidence of linkage. © 1993 Wiley-Liss, Inc.     

Depression and anxiety in people with inflammatory bowel disease

STUDY OBJECTIVE—To determine whether depression or anxiety co-occurs with ulcerative colitis (UC) or Crohn's disease (CD) more often than expected by chance, and, if so, whether the mental disorders generally precede or follow the inflammatory bowel diseases (IBD).
DESIGN—Nested case-control studies using a database of linked hospital record abstracts.
SETTING—Southern England.
MAIN RESULTS—Both depression and anxiety preceded UC significantly more often than would be predicted from the control population's experience. The associations were strongest when the mental conditions were diagnosed shortly before UC, although the association between depression and UC was also significant when depression preceded UC by five or more years. Neither depression nor anxiety occurred before CD more often than expected by chance. However, depression and anxiety were significantly more common after CD; the associations were strongest in the year after the initial record of CD. UC was followed by anxiety, but not by depression, more often than expected by chance and, again, the association was strongest within one year of diagnosis with UC.
CONCLUSIONS—The concentration of risk of depression or anxiety one year or less before diagnosis with UC suggests that the two psychiatric disorders might be a consequence of early symptoms of the as yet undiagnosed gastrointestinal condition. The data are also, however, compatible with the hypothesis that the psychiatric disorders could be aetiological factors in some patients with UC. Most of the excess anxiety or depression diagnosed subsequent to diagnosis of IBD occurs during the year after IBD is diagnosed and the probable explanation is that the mental disorders are sequelae of IBD.


Keywords: record linkage; ulcerative colitis; Crohn's disease; anxiety; depression     

Evidence for a dominant gene mechanism underlying coeliac disease in the west of Ireland

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus. To address this controversy, we examined the association of CD with HLA in 39 families from the West of Ireland. Previous studies have shown that the prevalence of CD and the frequencies of the HLA antigens associated with it are higher in this population than in most others. Analysis of the data revealed a significant excess of concordant sib-pairs with two HLA haplotypes in common and an excess of discordant pairs with no haplotype in common. Chi-square tests confirmed a highly significant association between HLA-B8 and CD. Both heterozygotes and homozygotes for B8 had a significantly increased risk of CD. The risk for homozygotes was slightly higher than for heterozygotes, although not significantly so. The segregation ratio for disease occurrence among sibs of probands was estimated to be 0.185 when neither parent is affected. We estimated a gene frequency of 0.003 for the disease allele (C) at the HLA-linked locus and of 0.648 for the disease allele (d) at the HLA-unlinked locus. Assuming that CCdd homozygotes are always affected and that only carriers of C who are homozygous dd can be affected, the disease was found to be completely penetrant in Ccdd heterozygotes. These results support dominance at the HLA-linked locus conferring susceptibility to CD. Possible reasons for the discrepancy between the West of Ireland and other populations are discussed.     

Gene-environment interactions in parkinsonism and Parkinson's disease: the Geoparkinson study

Objectives

To investigate associations of Parkinson''s disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene‐environment interaction effects that modify risk.

Methods

A case‐control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status. CYP2D6, PON1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO‐A, MAO‐B, SOD 2, EPHX,DAT1, DRD2 and NAT2 were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders.

Results

There was a modest but significant association between MAO‐A polymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene‐environment analyses did not show significant interaction effects. There were possible interaction effects between GSTM1 null genotype and solvent exposure (which were stronger when limited to PD cases only).

Conclusions

Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene‐environment interactions. This large study was sufficiently powered to examine these aspects. GSTM1 null subjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene‐environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.     

Cognition enhancing effect of the aqueous extract of Cinnamomum zeylanicum on non-transgenic Alzheimer's disease rat model: Biochemical,histological, and behavioural studies

Objective: Several dietary supplements are actively being tested for their dual role of alleviating the metabolic perturbations and restricting the consequent cognitive dysfunctions seen in neurodegenerative disorders such as Alzheimer's disease (AD). The aim of the current study was to assess the influence of aqueous extract of cinnamon (CE) on the monosodium glutamate-induced non-transgenic rat model of AD (NTAD) established with insulin resistance, hyperglycaemia, neuronal loss, and cognitive impairment at a very early stage of life.

Methods: The experimental design included oral administration of CE (50?mg/kg body weight) for 20 weeks to 2-month and 10-month-old NTAD rats. Following the treatments, the animals attained 7 and 15 months of age, respectively. They were then subjected to behavioural testing, biochemical analysis, and stereology experiments.

Results: The results demonstrated that CE treatment improved the insulin sensitivity, increased phosphorylated glycogen synthase kinase-3β (pGSK3β), inhibited the cholinesterase activity, and improved the learning ability in NTAD rats. Histological evaluation has shown an increase in neuron count in the DG sub-field of hippocampus upon treatment with CE.

Discussion: These beneficial effects of CE are suggestive of considering cinnamon as a dietary supplement in modulating the metabolic changes and cognitive functions.     

Two new approaches toward linkage heterogeneity of FAD: Two-locus models and age of onset as a discriminator

We present two new approaches to the problem of genetic heterogeneity encountered in linkage analysis of familial Alzheimer's disease. We used two-locus models to represent the possible existence of two disease genes while allowing for intrafamilial heterogeneity, and modeled the occurrence of the early onset form of the disease with epistasis. We developed a mixture model of heterogeneity where the early and late onset family types can be either linked to chromosome 19, 21, or unlinked, and where it is not necessary to arbitrarily preclassify a family into an early or late onset family type. © 1993 Wiley-Liss, Inc.     

No association between the very low density lipoprotein receptor gene and late-onset Alzheimer's disease nor interaction with the apolipoprotein E gene in population-based and clinic samples

It is now commonly known that possession of one of the three common alleles of the apolipoprotein E (APOE) gene (allele ϵ4) confers an increased risk for both familial and sporadic Alzheimer's disease (AD), and that this risk is dose-dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, are under investigation. One such gene, the very low density lipoprotein receptor (VLDL-R) gene, was reported by Okuizumi et al. to be independently associated with AD in a Japanese population, but not interactive with the APOE4 conferred risk. Their clinic-based data set demonstrated a 2-fold increased risk conferred by the 5-repeat allele of a polymorphism in VLDL-R. As recruitment from a clinic rather than a population-based sample may result in a distortion of allele frequencies, as has been shown with APOE allele frequencies, it is important to investigate this association in a population-based study. We have genotyped both population and clinic-based AD data sets at this VLDL-R polymorphism, and we find no independent association between the VLDL-R gene and the occurrence of AD in either sample. Further, despite the biochemical relationship between the VLDL-R and APOE proteins, we find no significant statistical interaction between the alleles at these loci. Genet. Epidemiol. 14:299–305,1997. © 1997 Wiley-Liss, Inc.     

Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies

Epidemiological evidence of an association between Alzheimer's disease (AD) and the most frequently studied occupational exposures--pesticides, solvents, electromagnetic fields (EMF), lead and aluminium--is inconsistent. Epidemiological studies published up to June of 2003 were systematically searched through PubMed and Toxline. Twenty-four studies (21 case-control and 3 cohort studies) were included. Median GQI was 36.6% (range 19.5-62.9%). Most of the case-control studies had a GQI of <50%. The study with the highest score was a cohort study. Likelihood of exposure misclassification bias affected 18 of the 24 studies. Opportunity for bias arising from the use of surrogate informants affected 17 studies, followed by disease misclassification (11 studies) and selection bias (10 studies). Eleven studies explored the relationship of AD with solvents, seven with EMF, six with pesticides, six with lead and three with aluminium. For pesticides, studies of greater quality and prospective design found increased and statistically significant associations. For the remaining occupational agents, the evidence of association is less consistent (for solvents and EMF) or absent (for lead and aluminium).     

Interaction between genetic and environmental risk factors for Alzheimer's disease: A reanalysis of case-control studies

To study the interaction among genetic and environmental risk factors, a reanalysis of case-control studies of Alzheimer's disease (AD) was conducted based on the original data of all studies carried out to January 1, 1990. Seven studies were included in the present analysis, comprising a total of 814 AD patients and 894 control subjects. When comparing those with a positive and negative family history of dementia, similar odds ratio were found for late maternal age [1.7; 95% confidence interval (0.6–4.8) vs. 2.0 (1.1–3.5)], head trauma [1.7 (0.7–4.2) vs. 1.9 (1.1–3.2)], and history of depression [2.0 (0.2–19.8) vs. 2.1 (0.8–1.7)]. This suggests a model in which these risk factors increase the risk for AD independent of family history of dementia. Among those with a positive family history of dementia, the odds ratios for family history of Down's syndrome [4.2 (0.9–20.0))] and of Parkinson's disease [3.3 (0.4–28.2)] tended to be higher than among those with a negative family history of dementia [2.6 (0.8–8.5) and 2.4 (0.8–7.0), respectively]. However, for both disorders the difference in odds ratio was not statistically significant. For history of cigarette smoking, there was no association to AD for those with no first degree relatives with dementia and an inverse relation with AD for those with a positive family history. Although in all analyses, family history of dementia remained significantly associated with AD in the absence of other factors, the odds ratio associated with family history of dementia tended to be lower for those with a positive smoking history, particularly for those with two or more affected relatives. These findings suggest that smoking may interact specifically with a genetically determined process. © 1994 Wiley-Liss, Inc.     

A review on therapeutic potentials of Trigonella foenum graecum (fenugreek) and its chemical constituents in neurological disorders: Complementary roles to its hypolipidemic,hypoglycemic, and antioxidant potential

Objectives: The growing rate of neurological disorders is a major concern in today's scenario. Today's research is focusing on therapeutic interventions providing benefits in these disorders. Presently, drugs of natural origin have gained more interest for the treatment of central nervous system disorders for their efficacy and less/ no side effects. This review is emphasizing the cited roles of Trigonella foenum graecum (fenugreek) and its constituents in different neurological manifestations.

Method: A review of the literature, relevant to the role of fenugreek and its major constituents including saponins and alkaloids in different neurological aspects and in delineating the health benefits, was conducted.

Results: The cited research acknowledged that fenugreek and its constituents exert positive influence on neurological health. Few studies have reported the beneficial role of fenugreek and its constituents like trigonelline in pathological symptoms of Alzheimer's disease. Similarly, other studies evidenced the neuroprotective, antidepressant, antianxiety as well as modulatory effect on cognitive functions and Parkinson's disease.

Discussion: Large populations are the sufferers of the neurological disorders, pointing the need for investigation of such therapeutic interventions which target and delay the underlying pathological hallmarks and exert positive influence on different neurological health problems. Hypolipidemic, hypoglycemic, antioxidant, and immunomodulatory effects of fenugreek and its constituents with their potential role in various neurological disorders were already reported. In future, it would be of even greater interest to further develop more effective dosage, supplementation period, and to evaluate the therapeutic potentials of fenugreek and its constituents in neurological disorders by exploring underlying cellular and molecular mechanisms.