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.

     

Synergistic effect of two HLA heterodimers in the susceptibility to celiac disease in Tunisia

The DR and DQ HLA genotypes of 94 Tunisian children affected with celiac disease are analyzed so that we can gain a better understanding of the HLA component of this disease. All of them carry at least one of two specific heterodimers: a DQ heterodimer, encoded by DQA1*0501, DQB1*0201 and/or a DR heterodimer, encoded by the nonpolymorphic gene DRA and the DRB4 gene. Quantifying the relative penetrances of all susceptible genotypes gives evidence for a synergistic effect of these two heterodimers and for a dose effect of the alleles encoding the β chains of these two heterodimers. The DR3DR7 individuals have the greatest risk. They present the two kinds of heterodimers and carry two DQB1*0201 alleles. Celiac disease is the first HLA-associated disease for which the at-risk genotypes are so well delineated. Genet. Epidemiol. 14:413–422,1997. © 1997 Wiley-Liss, Inc.     

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.     

Confronting complexity in late-onset Alzheimer disease: application of two-stage analysis approach addressing heterogeneity and epistasis

Common diseases with a genetic basis are likely to have a very complex etiology, in which the mapping between genotype and phenotype is far from straightforward. A new comprehensive statistical and computational strategy for identifying the missing link between genotype and phenotype has been proposed, which emphasizes the need to address heterogeneity in the first stage of any analysis and gene-gene interactions in the second stage. We applied this two-stage analysis strategy to late-onset Alzheimer disease (LOAD) data, which included functional and positional candidate genes and markers in a region of interest on chromosome 10. Bayesian classification found statistically significant clusterings for independent family-based and case-control datasets, which used the same five markers in leucine-rich repeat transmembrane neuronal 3 (LRRTM3) as the most influential in determining cluster assignment. In subsequent analyses to detect main effects and gene-gene interactions, markers in three genes--urokinase-type plasminogen activator (PLAU), angiotensin 1 converting enzyme (ACE) and cell division cycle 2 (CDC2)--were found to be associated with LOAD in particular subsets of the data based on their LRRTM3 multilocus genotype. All of these genes are viable candidates for LOAD based on their known biological function, even though PLAU, CDC2 and LRRTM3 were initially identified as positional candidates. Further studies are needed to replicate these statistical findings and to elucidate possible biological interaction mechanisms between LRRTM3 and these genes.     

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.     

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.     

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.     

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.     

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     

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.     

Asian Americans’ concerns and plans about Alzheimer's disease: The role of exposure,literacy and cultural beliefs

Responding to the increase of the Asian American population and the growing imperative to address issues on Alzheimer's disease (AD) in diverse populations, this study examined Asian Americans’ concerns about AD (both concerns about one's own development of AD and about becoming an AD caregiver) and plans for AD. Focus was given on exploring the role of AD exposure, AD literacy and cultural beliefs about AD in predicting AD‐related concerns and plans. Using data from 2,609 participants in the 2015 Asian American Quality of Life survey (aged 18–98), logistic regression models of three outcome measures (concerns about one's own development of AD, concerns about becoming an AD caregiver and plans about AD) were estimated. AD exposure and literacy (perceived knowledge and awareness of services) were common predictors of all three outcomes. Beliefs that associate AD with a normal part of ageing and a matter of fate increased the odds of having AD concerns. The odds of having AD plans were found to be higher among those with such concerns. Findings not only identified the factors associated with the concerns and plans about AD but also informed ways to develop targeted AD interventions for Asian Americans.     

The effect of dental care on cardiovascular disease outcomes: an application of instrumental variables in the presence of heterogeneity and self-selection

Studies show a relationship between oral inflammatory processes and cardiovascular risk factors, suggesting that dental care may reduce the risk of cardiovascular disease (CVD) events. However, due to the differences between men and women in the development and presentation of CVD, such effects may vary by sex. We use a valid set of instrumental variables to evaluate these issues and include a test of essential heterogeneity. CVD events include new occurrences of heart attack (including death from heart attack), stroke (including death from stroke), angina, and congestive heart failure. Controls include age, race, education, marital status, foreign birthplace, and cardiovascular risk factors (health status, body mass index, alcohol use, smoking status, diabetes status, high-blood-pressure status, physical activity, and depression). Our analysis finds no evidence of essential heterogeneity. We find the minimum average treatment effect for women to be -0.01, but find no treatment effect for men. This suggests that women who receive dental care may reduce their risk of future CVD events by at least one-third. The findings may only apply to married middle-aged and older individuals as the data set is only representative for this group.     

Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds

The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD.     

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.