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S L Slager

Publications and source records attributed to S L Slager.

At least 19 recordsLinked to original sources
PubMed2004

Investigation of serotonin-related genes in antidepressant response.

In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.

Antidepressive Agents, Second-Generation↗
PubMed2003

Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q.

Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P<.00001). In addition, we report suggestive evidence for linkage on chromosome 4 (D4S403, P=.00012). The results of previous findings, together with our results, provide strong evidence that chromosome 19 harbors a gene for tumor aggressiveness.

Chromosome Mapping↗
PubMed2003

Candidate-gene association studies with pedigree data: controlling for environmental covariates.

Case-control studies provide an important epidemiological tool to evaluate candidate genes. There are many different study designs available. We focus on a more recently proposed design, which we call a multiplex case-control (MCC) design. This design compares allele frequencies between related cases, each of whom are sampled from multiplex families, and unrelated controls. Since within-family genotype correlations will exist, statistical methods will need to take this into account. Moreover, there is a need to develop methods to simultaneously control for potential confounders in the analysis. Generalized estimating equations (GEE) are one approach to analyze this type of data; however, this approach can have singularity problems when estimating the correlation matrix. To allow for modeling of other covariates, we extend our previously developed method to a more general model-based approach. Our proposed methods use the score statistic, derived from a composite likelihood. We propose three different approaches to estimate the variance of this statistic. Under random ascertainment of pedigrees, score tests have correct type I error rates; however, pedigrees are not randomly ascertained. Thus, through simulations, we test the validity and power of the score tests under different ascertainment schemes, and an illustration of our methods, applied to data from a prostate cancer study, is presented. We find that our robust score statistic has estimated type I error rates within the expected range for all situations we considered whereas the other two statistics have inflated type I error rates under nonrandom ascertainment schemes. We also find GEE to fail at least 5% of the time for each simulation configuration; at times, the failure rate reaches above 80%. In summary, our robust method may be the only current regression analysis method available for MCC data.

Case-Control Studies↗
PubMed2002

The IDDM13 region containing the insulin-like growth factor binding protein-5 (IGFBP5) gene on chromosome 2q33-q36 and the genetic susceptibility to rheumatoid arthritis.

We considered that the constitutive over-expression by cultured rheumatoid arthritis (RA) fibroblast-lineage synoviocytes of genes like IGFBP5 could indicate new candidate susceptibility genes. IGFBP5 is located in a region where an insulin-dependent diabetes mellitus (IDDM) susceptibility locus, IDDM13 (2q33-q36), has been mapped. Previous evidence that non-MHC IDDM loci overlap RA susceptibility loci made IGFBP5 and its region an interesting candidate locus which was tested for linkage. Forty-nine sibships (2-4 affected siblings per sibship) with RA were genotyped with microsatellite markers covering an 11.2 cM interval in the IGFBP5/IDDM13 region. Both the two-point LOD scores and a 'nonparametric' allele-sharing analysis revealed no evidence for linkage (max LOD = 0.54, P = 0.5, respectively). Adjustments for the presence of 'shared-epitope' alleles did not significantly change the LOD scores. These results suggest that, despite the involvement of the 2q33-q36 chromosomal region in another organ-specific autoimmune disease, it is unlikely that this region harbors a RA susceptibility locus.

Arthritis, Rheumatoid↗
PubMed2001

Role of HPC2/ELAC2 in hereditary prostate cancer.

The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.

Adult↗
PubMed2001

Evaluation of candidate genes in case-control studies: a statistical method to account for related subjects.

Traditional case-control studies provide a powerful and efficient method for evaluation of association between candidate genes and disease. The sampling of cases from multiplex pedigrees, rather than from a catchment area, can increase the likelihood that genetic cases are selected. However, use of all the related cases without accounting for their biological relationship can increase the type I error rate of the statistical test. To overcome this problem, we present an analysis method that is used to compare genotype frequencies between cases and controls, according to a trend in proportions as the dosage of the risk allele increases. This method uses the appropriate variance to account for the correlated family data, thus maintaining the correct type I error rate. The magnitude of the association is estimated by the odds ratio, with the variance of the odds ratio also accounting for the correlated data. Our method makes efficient use of data collected from multiplex families and should prove useful for the analysis of candidate genes among families sampled for linkage studies. An application of our method, to family data from a prostate cancer study, is presented to illustrate the method's utility.

Alleles↗
PubMed2001

Power comparisons between the TDT and two likelihood-based methods.

We compare the statistical power of the transmission disequilibrium test (TDT) with that of two likelihood-based linkage tests, the classical LOD score and a modified LOD score in which a linkage disequilibrium (LD) parameter is incorporated into the likelihood (LD-LOD). We hypothesize that, when LD is present, the LD-LOD will have the greatest power of the three tests because the TDT breaks a multiplex pedigree into triads, and the LOD score has previously been shown to have lower power when LD is present but not accounted for. We test this hypothesis using a simulation study in which we generate affected sib-pair (ASP) pedigrees under a range of genetic models, varying the genotypic relative risk (GRR) from 6 to 16. Because the likelihood-based tests require that a genetic model be specified, we compare the tests under two scenarios. First, we assume the true genetic model in the analysis, and second, we compare the tests when the LD-LOD (LOD) is maximized over two wrong genetic models. For the generating models we considered, we find that the LD-LOD has greater power than the TDT even when the genetic models is mis-specified and the results corrected for multiple tests. Extreme differences occur under the multiplicative and dominant models, for which the difference in power is as high as 40% at complete LD. The LOD score provides the lowest power in the presence of LD for the range of GRR considered here.

Adult↗
PubMed2001

Genome scan for linkage to asthma using a linkage disequilibrium-lod score test.

We report a genome-wide linkage study of asthma on the German and Collaborative Study on the Genetics of Asthma (CSGA) data. Using a combined linkage and linkage disequilibrium test and the nonparametric linkage score, we identified 13 markers from the German data, 1 marker from the African American (CSGA) data, and 7 markers from the Caucasian (CSGA) data in which the p-values ranged between 0.0001 and 0.0100. From our analysis and taking into account previous published linkage studies of asthma, we suggest that three regions in chromosome 5 (around D5S418, D5S644, and D5S422), one region in chromosome 6 (around three neighboring markers D6S1281, D6S291, and D6S1019), one region in chromosome 11 (around D11S2362), and two regions in chromosome 12 (around D12S351 and D12S324) especially merit further investigation.

Adult↗
PubMed2001

Markov chain Monte Carlo linkage analysis: effect of bin width on the probability of linkage.

We analyzed part of the Genetic Analysis Workshop (GAW) 12 simulated data using Monte Carlo Markov chain (MCMC) methods that are implemented in the computer program Loki. The MCMC method reports the "probability of linkage" (PL) across the chromosomal regions of interest. The point of maximum PL can then be taken as a "location estimate" for the location of the quantitative trait locus (QTL). However, Loki does not provide a formal statistical test of linkage. In this paper, we explore how the bin width used in the calculations affects the max PL and the location estimate. We analyzed age at onset (AO) and quantitative trait number 5, Q5, from 26 replicates of the general simulated data in one region where we knew a major gene, MG5, is located. For each trait, we found the max PL and the corresponding location estimate, using four different bin widths. We found that bin width, as expected, does affect the max PL and the location estimate, and we recommend that users of Loki explore how their results vary with different bin widths.

Chromosome Mapping↗
PubMed2001

Stoppage: an issue for segregation analysis.

Segregation analysis assumes that the observed family-size distribution (FSD), i.e., distribution of number of offspring among nuclear families, is independent of the segregation ratio p. However, for certain serious diseases with early onset and diagnosis (e.g., autism), parents may change their original desired family size, based on having one or more affected children, thus violating that assumption. Here we investigate "stoppage," the situation in which such parents have fewer children than originally planned. Following Brookfield et al. [J Med Genet 25:181-185, 1988], we define a stoppage probability d that after the birth of an affected child, parents will stop having children and thus not reach their original desired family size. We first derive the full correct likelihood for a simple segregation analysis as a function of p, d, and the ascertainment probability pi. We show that p can be estimated from this likelihood if the FSD is known. Then, we show that under "random" ascertainment, the presence of stoppage does not bias estimates of p. However, for other ascertainment schemes, we show that is not the case. We use a simulation study to assess the magnitude of bias, and we demonstrate that ignoring the effect of stoppage can seriously bias the estimates of p when the FSD is ignored. In conclusion, stoppage, a realistic scenario for some complex diseases, can represent a serious and potentially intractable problem for segregation analysis.

Family Characteristics↗
PubMed2001

No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder.

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Cholecystokinin↗
PubMed2001

Case-control studies of genetic markers: power and sample size approximations for Armitage's test for trend.

The association of a candidate gene with disease can be efficiently evaluated by a case-control study in which allele frequencies are compared for diseased cases and unaffected controls. However, when the distribution of genotypes in the population deviates from Hardy-Weinberg proportions, the frequency of genotypes--rather than alleles--should be compared by the Armitage test for trend. We present formulas for power and sample size for studies that use Armitage's trend test. The formulas make no assumptions about Hardy-Weinberg equilibrium, but do assume random ascertainment of cases and controls, all of whom are independent of one another. We demonstrate the accuracy of the formulas by simulations.

Algorithms↗
PubMed2000

Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.

Familial primary pulmonary hypertension is a rare autosomal dominant disorder that has reduced penetrance and that has been mapped to a 3-cM region on chromosome 2q33 (locus PPH1). The phenotype is characterized by monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles. These lesions lead to elevated pulmonary-artery pressures, right-ventricular failure, and death. Although primary pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs, including phentermine-fenfluramine. We genotyped 35 multiplex families with the disorder, using 27 microsatellite markers; we constructed disease haplotypes; and we looked for evidence of haplotype sharing across families, using the program TRANSMIT. Suggestive evidence of sharing was observed with markers GGAA19e07 and D2S307, and three nearby candidate genes were examined by denaturing high-performance liquid chromatography on individuals from 19 families. One of these genes (BMPR2), which encodes bone morphogenetic protein receptor type II, was found to contain five mutations that predict premature termination of the protein product and two missense mutations. These mutations were not observed in 196 control chromosomes. These findings indicate that the bone morphogenetic protein-signaling pathway is defective in patients with primary pulmonary hypertension and may implicate the pathway in the nonfamilial forms of the disease.

Amino Acid Sequence↗
PubMed2000

Effect of allelic heterogeneity on the power of the transmission disequilibrium test.

Due in part to an influential paper by Risch and Merikangas [(1996) Science 273:1516-1517], which suggested that disequilibrium tests would have greater power to detect genes of small effect than would linkage tests, interest in the use of the Transmission Disequilibrium Test (TDT) as an analysis tool for genomewide studies is steadily growing. However, the paper by Risch and Merikangas made several simplifying assumptions. One such assumption was that the underlying gene showed allelic homogeneity, and another was that the allele being measured was the actual susceptibility allele. Here we investigate the effect of allelic heterogeneity on the power of the TDT using multiplicative, additive, dominant, and recessive modes of inheritances in the context of a genomewide study. We further distinguish two cases: first, that the marker alleles are the actual susceptibility alleles, and second, that alleles are measured at a marker linked to the disease gene with zero recombination. We consider two family structures, either a single affected offspring (SAO) and two parents, or an affected sib-pair (ASP) and two parents. We find that, as expected, the power of the TDT declines as the number of susceptibility alleles at the locus being tested increases and the effect on power can be substantial. When a linked marker is measured rather than a susceptibility allele itself, sample sizes reach unattainable levels when as few as two susceptibility alleles are present. Across all the models we consider, the required number of families for a TDT with ASP sampling varies from 19 to over a million families. Thus, the TDT may not be an optimal test in the context of genomic screens under more biologically realistic assumptions.

Alleles↗
PubMed1998

Development of smokeless tobacco-induced oral mucosal lesions.

This study examined clinical and inflammatory mediator parameters during the development of snuff-induced mucosal lesions. Nineteen smokeless tobacco (ST) users placed moist snuff at designated new placement sites over either a 2- or 7-day period. By day 2, the predominant clinical alteration was an erythematous reaction, and one-third of the subjects demonstrated white striations in combination with erythema or ulceration. By 7 days, 56% of the subjects displayed white striated lesions. Tissue concentrations (pg/mg) of IL-1beta were 4.6+/-1.6 at new placement sites as compared with 0.7+/-0.4 at control sites (P<0.05). PGE2 and IL-1alpha concentrations also were significantly higher (P<0.05) at new placement sites as compared with control sites (9.4+/-2.2 vs 4.1+/-0.7 and 6.2+/-1.3 vs 3.2+/-0.7, respectively). In view of the recognized role of PGE2 and IL-1 in immune and inflammatory functions, these mediators may play a role in the pathogenesis of clinical alterations at ST placement sites.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1998

Patterns of dietary fluoride supplement use during infancy.

OBJECTIVES: This paper reports on patterns of dietary fluoride supplement use during infancy. METHODS: Data were collected by mail for a birth cohort (n = 1,072) studied at 6 weeks and 3, 6, 9, and 12 months of age. RESULTS: Percentages using supplements were 13.7 at 6 weeks, 13.4 at 3 months, 16.5 at 6 months, 13.0 at 9 months, and 12.1 at 12 months. Among those receiving supplements, mean proportions of weeks that supplements were received during the different time periods varied from 0.59 to 0.80. Number of days per week receiving supplements averaged 4.8 to 5.0. Mean fluoride dosages when supplements were received were 0.22 mg to 0.24 mg. Estimated average daily fluoride ingestion per day (among those receiving supplements during that time period and factoring in those days and weeks that supplements were not received) was 0.11 mg at 6 weeks, 0.15 mg at 3 months, 0.12 mg at 6 months, 0.11 mg at 9 months, and 0.14 mg at 12 months. Among the subset of 129 children with complete data at all time points who used supplements sometime during their first year of life, mean annual daily supplement dosage was 0.07 mg fluoride, with 75 percent having less than or equal to 0.10 mg. Those infants with mothers and fathers with more education were more likely to receive supplements. CONCLUSIONS: Group average use of fluoride supplements was fairly consistent over the 12 months; however, individual patterns varied substantially. Estimated actual mean daily fluoride intake when including days that supplements were not received was substantially less than the recommended 0.25 mg per day.

Adult↗
PubMed1997

Investigating the numerical effects of ascertainment bias in linkage analysis: development of methods and preliminary results.

It is general practice to have nonsingle ascertainment of pedigrees for linkage studies, along with intrafamilial sampling that is dependent on who among the related individuals was initially ascertained (Proband dependent or PD sampling). Vieland and Hodge [1995; 1996] have shown that under these conditions, the likelihood used in calculating the lod score is not strictly correct and can produce asymptotically biased estimates of the recombination fraction, theta. However they speculated that this bias would be small in most applications. This paper presents preliminary work aimed at quantifying the numerical magnitude of the bias introduced by PD sampling and nonsingle ascertainment in linkage analysis. We considered five generating models where we varied the ascertainment procedure, intrafamilial sampling scheme, and the sample size for each model. In this limited initial set of simulations, asymptotic bias in theta appears to be trivial, while PD sampling procedures can increase the efficiency of theta. These preliminary results support the view that the advantages of unsystematic ascertainment may offset any small estimation bias that may arise.

Bias↗