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S Premkumar

Publications and source records attributed to S Premkumar.

12 recordsLinked to original sources
PubMed2000

Association between angiotensin-converting enzyme and Alzheimer disease.

BACKGROUND: Angiotensin-converting enzyme has been reported to show altered activity in patients with neurologic diseases. An insertion-deletion polymorphism in ACE has recently been linked to heart disease, cerebrovascular disease, and AD. OBJECTIVE: To determine whether the angiotensin-converting enzyme (ACE) is associated with risk of Alzheimer disease (AD). METHODS: We investigated the ACE polymorphism as a potential risk factor for AD in 151 patients with AD and 206 ethnically matched controls from Russia and in 236 patients with AD and 169 controls from North America by means of allele association methods and logistic regression. RESULTS: None of the ACE genotypes was associated with increased susceptibility to AD in the total sample or in subsets stratified by apolipoprotein E gene (APOE) epsilon4 status. However, the D allele was more frequent among AD cases between ages 66 and 70 years compared with controls in both the Russian (P = .02) and North American (P = .001) datasets. In this age group, the effect of D (odds ratio, 11.2; 95% confidence interval, 2.9-44.0) appeared to be independent of and equal or greater in magnitude to the effect of APOE epsilon4 (odds ratio, 7.8; 95% confidence interval, 3.5-7.4). CONCLUSIONS: Our results suggest that APOE and ACE genotypes may be independent risk factors for late-onset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed.

Aged↗
PubMed1999

Alpha-2 macroglobulin gene in early- and late-onset Alzheimer disease.

Alpha-2-macroglobulin (A2M) is a proteinase inhibitor that is present in senile plaques and may play a role in metabolism of amyloid beta (A beta) peptide. Recently it was reported that inheritance of the deletion allele (A2M-2) confers increased risk for late-onset Alzheimer disease (AD) with significance of this effect similar to the epsilon4 allele of apolipoprotein E (APOE). We examined the distribution of A2M genotypes and alleles in a cohort of 146 AD patients and 160 age-matched non-demented individuals. There was no evidence for association in the total sample or in subsets stratified by age or APOE epsilon4 status. These results suggest that this polymorphism is not a strong genetic risk factor for either early- or late-onset forms of the disorder. However, they do not exclude the possibility that an AD susceptibility allele is located elsewhere in A2M or a nearby gene.

Age Factors↗
PubMed1999

Power of concordant versus discordant sib pairs at different penetrance levels.

Knowing the answers, we used the GAW11 data set to compare the power and efficiency of discordant versus concordant affected sib pairs for qualitative traits at different levels of penetrance. Samples of 200 concordant sib pairs outperformed discordant sib pairs for low penetrance (40%) and 70% penetrance models while at 90% penetrance they performed equally well. Increasing the sample size of discordant sib pairs to twice that of concordant pairs was not enough to reach the power of concordant sib pairs at the 40% and 70% penetrance models. For low penetrance using a combination of concordant and discordant sib pairs resulted in higher power than using discordant sib pairs alone. At 90% penetrance, the power of concordant and discordant sib pairs was similar in the region close to the gene while concordant sib pairs performed better at locations further from the gene.

Genetic Linkage↗
PubMed1999

Stratification techniques to explore genotype environment interactions.

Linkage analysis was performed on the GAW11 Problem 2 data set using stratification to explore the effects of the environmental risk factors and the differences between mild and severe phenotypes. Analysis of the four study populations stratified by the two risk factors identified regions on chromosomes 3 and 5 with significant evidence for linkage. Other loci were sought by removing families consistent with linkage to the chromosome 3 locus. Our studies identified a locus on chromosome 3 (markers 43-46) associated with the mild phenotype in the presence of risk factor 1 and with the severe phenotype independent of risk factor 1. This suggests that distinct allelic variants at the chromosome 3 locus may cause different forms of disease. The locus identified on chromosome 5 (markers 36-39) was linked to the severe phenotype, but exposure to factor 1 or 2 may have a protective effect. The regions on chromosomes 3 and 5 appeared to have independent roles in disease etiology. Evidence for two loci on chromosome 1 linked to the mild form was found. The methods successfully identified linkages and interaction consistent with the generating model.

Environment↗
PubMed1998

Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity.

CONTEXT: Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. OBJECTIVE: To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. DESIGN: Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. SETTING: Clinical populations in the continental United States, Canada, Argentina, and Italy. PATIENTS: Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. MAIN OUTCOME MEASURE: Presence of an APOE epsilon4 allele among affected family members. RESULTS: Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). CONCLUSIONS: Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.

Adult↗
PubMed1998

Absence of association between Alzheimer disease and the -491 regulatory region polymorphism of APOE.

A novel polymorphism (-491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the -491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE epsilon2/epsilon3/epsilon4 polymorphism.

Aged↗
PubMed1998

Association between bleomycin hydrolase and Alzheimer's disease in caucasians.

A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with non-demented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controlling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.

Aged↗
PubMed1998

Analysis of the butyrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease.

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re-examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.

Aged↗
PubMed1995

Effects of marker information on sib-pair linkage analysis of a rare disease.

Model-free sib-pair linkage analysis was used to screen the GAW9-Problem 1 data set for evidence of linkage of a rare disease to any of 360 highly polymorphic marker loci. Negative regressions nominally significant at the alpha = 0.05 level were obtained for 44 markers; however all of these proved to be Type I errors. None of the four disease loci were detected by sib-pair linkage, which was not surprising, given the particular model and sampling scheme used to generate these data. Neither deleting parental marker genotypic information nor misspecifying marker allele frequency estimates substantially increased the Type I error rate. A two-stage testing procedure using a 10 or 20 cM map and a liberal first stage significance level gave the same overall results as a one-stage 2 cM map but required only about 42% or 22% as many markers, respectively.

Alleles↗
PubMed1991

Disseminated tuberculosis in the acquired immunodeficiency syndrome era.

To assess the influence of human immunodeficiency virus type 1 (HIV)-induced immunodeficiency on the clinical, radiographic, and pathologic features of disseminated tuberculosis (TB), we studied 79 patients presenting in 1984 through 1987 with miliary or focal disseminated disease due to Mycobacterium tuberculosis, as well as 4 additional non-HIV patients diagnosed after 1987. Clinically defined acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) was present in 51 (Group 1). A total of 20 had TB unrelated to HIV disease (Group 2). The remaining 12 were excluded because the role of HIV could not be determined. Clinical features were similar between groups aside from younger age; lower hemoglobin, total leukocyte, lymphocyte, and platelet counts; and more frequent tuberculin anergy (90 versus 40%) in AIDS/ARC patients (p less than or equal to 0.03). Chest radiographs showed a miliary pattern in about half of each group. Pleural effusion occurred only in AIDS/ARC patients (24%, p = 0.02), but intrathoracic lymphadenopathy was present in about a third of each group. Tissue biopsies (n = 70) usually revealed necrotizing granulomatous inflammation in each group, with a tendency to greater necrosis and more numerous acid-fast bacilli in Group 1. Granulomas were usually poorly formed in AIDS/ARC patients (59 versus 18%, p = 0.01). Autopsy of 9 AIDS/ARC patients with overwhelming miliary TB revealed a "nonreactive" histologic pattern with poorly organized or absent granulomas, extensive necrosis, and numerous bacilli. HIV-related disseminated TB causes a major constitutional illness with a high short-term mortality (25%).(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1989

A reverse passive haemagglutination test for detection of Japanese encephalitis virus antigens in cerebrospinal fluid.

A rapid sensitive and specific reverse passive haemagglutination test (RPHA) was developed for the detection of Japanese encephalitis virus (JEV) antigens in human cerebrospinal fluid (CSF). Sheep red cells were sensitized with five monoclonal antibodies (109, 112, 203, 204 and 301) reactive with envelope glycoprotein of JEV. Viral antigens were detected in CSF from 35 of 58 (60%) clinical cases of JE when the five MAb coated cells were used in combination. An IgM capture ELISA detected JEV specific antibodies in CSF among 52 of these 58 cases (90%). While 29 specimens contained both antigen and IgM antibodies, 23 had only IgM antibodies and 6 had only antigen. RPHA proved valuable for detection of viral antigens in CSF samples obtained within 10 days after onset of clinical symptoms. Amongst the five MAbs used, the individual antigen detection rates were 44, 12, 43, 12 and 36%, for MAbs 109, 112, 203, 204 and 301, respectively.

Animals↗