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Peter Kraft

Publications and source records attributed to Peter Kraft.

At least 37 records · Page 2Linked to original sources
PubMed2005

CYP19 (aromatase) haplotypes and endometrial cancer risk.

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)(n) repeat polymorphism in intron IV as well as a 3'UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case-control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989-1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning > 123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency > or = 5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13-2.48) to 2.07 (95% CI 1.33-3.23), comparing variant allele carriers to wild-type homozygotes. We observed significant interactions between menopausal status and 2 of the high-risk loci (p = 0.03 and p < 0.01), with > 2-fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high-frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women.

Adult↗
PubMed2005

Polymorphisms in the CC-chemokine receptor-2 (CCR2) and -5 (CCR5) genes and risk of coronary heart disease among US women.

OBJECTIVE: Genetic variation in CC-chemokine receptor-2 (CCR2) and -5 (CCR5), and their common haplotypes, acting through inflammatory responses, may affect atherosclerosis and risk of coronary heart disease (CHD). METHOD AND RESULTS: We examined seven common variants in the CCR2 and CCR5 loci and risk of CHD among women in the Nurses' Health Study. During 8 years of follow-up, we documented 248 incident cases of nonfatal myocardial infarction and fatal CHD, and matched controls 2:1 based on age and smoking. The distribution of alleles was similar between cases and controls. The haplotype-specific odds ratios (ORs) were not statistically significant nor was the globally-adjusted p-value (p=0.61). However, there was a statistically significant association for CCR5-Delta32 and A58755G (rs2856758) between cases and controls comparing age of onset <55 and >or=55 years. For Delta32, the OR for having the variant was 0.12 (0.02-0.76) for age <55, and 1.14 (0.69-1.88) for age >or=55 years (p, interaction=0.04). The CCR5-Delta32 was in linkage disequilibrium with 58755G, and a similar association was observed for having the 58755G. CONCLUSIONS: In this population, CCR2-CCR5 haplotypes were not associated with risk of CHD. However, our data suggest a strong inverse association for certain CCR5 variants and early age of CHD onset.

Adult↗
PubMed2005

Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques.

Population-based case-control studies measuring associations between haplotypes of single nucleotide polymorphisms (SNPs) are increasingly popular, in part because haplotypes of a few "tagging" SNPs may serve as surrogates for variation in relatively large sections of the genome. Due to current technological limitations, haplotypes in cases and controls must be inferred from unphased genotypic data. Using individual-specific inferred haplotypes as covariates in standard epidemiologic analyses (e.g., conditional logistic regression) is an attractive analysis strategy, as it allows adjustment for nongenetic covariates, provides omnibus and haplotype-specific tests of association, and can estimate haplotype and haplotype x environment interaction effects. In principle, some adjustment for the uncertainty in inferred haplotypes should be made. Via simulation, we compare the performance (bias and mean squared error of haplotype and haplotype x environment interaction effect estimates) of several analytic strategies using inferred haplotypes in the context of matched case-control data. These strategies include using only the most likely haplotype assignment, the expectation substitution approach described by Stram et al. ([2003b] Hum. Hered. 55:179-190) and others, and an improper version of multiple imputation. For relatively uncomplicated haplotype structures and moderate haplotype relative risks (</=2), all methods performed comparably well (small bias with appropriately-sized confidence intervals). For larger relative risks, the most likely haplotype and multiple imputation strategies showed noticeable bias towards the null; the expectation substitution strategy still performed well. When there was more uncertainty in the inferred haplotypes, the most likely and multiple imputation strategies showed even more bias towards the null, while the expectation substitution method had slightly smaller than nominal confidence intervals for larger relative risks (>/=5). An application to progesterone-receptor haplotypes and endometrial cancer further illustrates that the performance of all these methods depends on how well the observed haplotypes "tag" the unobserved causal variant.

Algorithms↗
PubMed2005

Polymorphisms in the 5' region of the CD14 gene are associated with eczema in young children.

BACKGROUND: Variants in the CD14 gene (CD14) are hypothesized to be associated with atopic disorders. However, most studies have only investigated one polymorphism in this gene. OBJECTIVE: We sought to study the association of 5 single nucleotide polymorphisms (SNPs) in the 5' flanking region of CD14 with eczema and serum IgE levels in young children. METHODS: We genotyped 5 SNPs in an approximately 6.5-kb region in the 5' region of CD14 in 344 2-year-old white children from 2 birth cohorts in the northeastern United States. We examined the relation of both single SNPs and haplotypes in CD14 with the atopic outcomes. RESULTS: Two SNPs were significantly associated with eczema. In dominant models adjusted for potential confounders, SNP rs2569193 was associated with significantly decreased risk for eczema (odds ratio [OR] for CT/TT vs CC, 0.5; 95% CI, 0.3-0.8), whereas SNP rs2569190 (also reported as the C-159T) was associated with significantly increased risk for eczema (OR for CT/TT vs CC, 2.3; 95% CI, 1.4-3.8). The CT/TT genotypes of SNP rs2569190 also had higher geometric means of serum IgE than the CC genotype (24.6 vs 15 IU/mL, P = .025). Haplotype analyses provided results similar to those of the single SNP analyses. CONCLUSIONS: Our results contradict previous reports that have found a protective effect of the T allele of SNP rs2569190 (C-159T) against atopic disorders. Nevertheless, these results confirm the importance of polymorphisms in CD14 in the development of atopy, and future studies of this gene region will need to account for linkage disequilibrium and environmental exposures unique to the study population.

5' Flanking Region↗
PubMed2004

Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer.

INTRODUCTION: Truncation mutations in the BRCA1 gene cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population and account for little of the overall incidence of sporadic breast cancer. METHOD: We used whole-gene resequencing data to select haplotype tagging single nucleotide polymorphisms, and examined the association between common haplotypes of BRCA1 and breast cancer in a nested case-control study in the Nurses' Health Study (1323 cases and 1910 controls). RESULTS: One haplotype was associated with a slight increase in risk (odds ratio 1.18, 95% confidence interval 1.02-1.37). A significant interaction (P = 0.05) was seen between this haplotype, positive family history of breast cancer, and breast cancer risk. Although not statistically significant, similar interactions were observed with age at diagnosis and with menopausal status at diagnosis; risk tended to be higher among younger, pre-menopausal women. CONCLUSIONS: We have described a haplotype in the BRCA1 gene that was associated with an approximately 20% increase in risk of sporadic breast cancer in the general population. However, the functional variant(s) responsible for the association are unclear.

Adult↗
PubMed2004

Case-sibling gene-association studies for diseases with variable age at onset.

Studies which compare cases to disease-free siblings are useful for assessing association between a genetic locus and a phenotypic trait, as they eliminate the possibility of confounding by population stratification. Many analytic methods for such family-based studies are based on a binary disease model. However, complex diseases have variable age at onset. Consequently, binary-outcome methods can be inefficient or biased. We review methods for analysing censored age-at-onset data from family studies, including stratified Cox regression and genotype-decomposition regression, an unstratified procedure which regresses age-at-onset on between- and within-family genotype components. We also introduce a retrospective likelihood for censored age-at-onset data, which requires an external estimate of the baseline hazard. Stratified Cox regression does not use controls who have not attained the age of their case sibling(s), potentially leading to a loss of efficiency. Both genotype-decomposition regression and the retrospective likelihood use these younger controls. We assess the performance of these methods via simulation studies. Stratified Cox regression and the retrospective likelihood have appropriate type I error rates in almost all situations studied; genotype-decomposition regression is often anti-conservative. Away from the null, confidence intervals for the relative risk derived from stratified Cox regression are anti-conservative when the disease is rare and case-rich families are sampled. The retrospective likelihood is more efficient than stratified Cox regression and its confidence intervals have correct coverage when the disease is rare or the estimate of the baseline hazard is reasonably accurate. These results suggest that when estimating genotype relative risks is the principal analytic goal, stratified Cox regression is appropriate as long as the disease is common; when the disease is rare, the retrospective likelihood may be more appropriate.

Age of Onset↗
PubMed2004

Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study.

INTRODUCTION: The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. METHODS: We conducted a nested case-control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. RESULTS: Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (chi2 = 3.43, five degrees of freedom, P = 0.63). CONCLUSION: There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk.

Adult↗
PubMed2004

Cell type-specific association of hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein accumulation and radiobiologic tumor hypoxia.

PURPOSE: The transcription factor subunit hypoxia-inducible factor-1 alpha (HIF-1 alpha) is currently discussed as a potential endogenous marker of tumor hypoxia to select patients for modified treatment. Despite an association of immunohistochemical HIF-1 alpha overexpression and poor prognosis after radiotherapy in many tumor entities, the reported pattern of HIF-1 alpha staining was often not consistent with tumor hypoxia. To explain this discrepancy, we studied the in vitro conditions under which HIF-1 alpha protein accumulates. METHODS AND MATERIALS: FaDu human pharyngeal carcinoma and HT 1080 human fibrosarcoma cells were treated with different schedules of in vitro hypoxia at 5%, 1%, and 0.1% O(2) and reoxygenation. HIF-1 alpha protein levels were determined in nuclear extracts. Cellular radiation sensitivity was assessed by clonogenic survival assay after single-dose irradiation at the above oxygen concentrations. RESULTS: In both cell lines, weak HIF-1 alpha expression was observed at 20% O(2) and after 10 min of hypoxia. Increased HIF-1 alpha protein levels were observed at 1 h of hypoxia, remained stable over 24 h, and decreased to baseline within 15 min of reoxygenation. HIF-1 alpha protein at 5% O(2) was half-maximal in FaDu but indistinguishable from 0.1% O(2) in HT 1080. A good correlation of HIF-1 alpha protein level and hypoxic radiation resistance, with equal ranking of data points by both assays, was observed in FaDu cells but not in HT 1080 cells. CONCLUSIONS: The ability of HIF-1 alpha to indicate radiobiologically relevant levels of tumor hypoxia seems to be cell type specific. This finding may explain the inconsistent results regarding the pattern of HIF-1 alpha expression in tumor sections.

Cell Hypoxia↗
PubMed2004

Evaluation of an end-tidal portable ETCO2 colorimetric breath indicator (COLIBRI).

Evaluation of tube position is important after in-hospital and prehospital emergency intubation. Colorimetric breath indicators are devices for immediate control of tube positioning by showing a color change according to end-tidal CO2 (ETCO2) concentrations. We hypothesized that colorimetric breath indicators can yield reliable results for confirmation of tube position. The aim of this study was to evaluate the effectiveness and safety of a new colorimetric breath indicator (Colibri, ICOR AB, Bromma, Sweden) in 147 patients during general anesthesia, in critically ill patients, during transport to in-hospital interventions, and in a study design after insertion of a second tube into the esophagus in long-term ventilated patients. The Colibri was attached between the respective airway and ventilatory tubing. Seventy-three patients were investigated during general anesthesia, 39 patients were observed during long-term ventilation with an average duration of 33 hours, in 15 patients during transport to an intervention for up to 4 hours, and in 20 long-term ventilated patients at the medical intensive-care unit after insertion of a second tube intentionally into the esophagus with the help of a laryngoscope. The Colibri worked well in all groups investigated and showed no false results in the group with tubes inserted into the trachea and esophagus. Data suggest that the Colibri might serve as a valuable tool for evaluating and controlling tube position. This device is independent of power supply or electronic equipment, portable, small, and immediately ready for use.

Adolescent↗
PubMed2004

RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order.

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal-fetal genotype incompatibility (MFG) test used in an earlier case-parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.

Birth Order↗
PubMed2003

Multiple imputation methods for longitudinal blood pressure measurements from the Framingham Heart Study.

Missing data are a great concern in longitudinal studies, because few subjects will have complete data and missingness could be an indicator of an adverse outcome. Analyses that exclude potentially informative observations due to missing data can be inefficient or biased. To assess the extent of these problems in the context of genetic analyses, we compared case-wise deletion to two multiple imputation methods available in the popular SAS package, the propensity score and regression methods. For both the real and simulated data sets, the propensity score and regression methods produced results similar to case-wise deletion. However, for the simulated data, the estimates of heritability for case-wise deletion and the two multiple imputation methods were much lower than for the complete data. This suggests that if missingness patterns are correlated within families, then imputation methods that do not allow this correlation can yield biased results.

Adult↗
PubMed2003

Multivariate variance-components analysis of longitudinal blood pressure measurements from the Framingham Heart Study.

Multivariate variance-components analysis provides several advantages over univariate analysis when studying correlated traits. It can test for pleiotropy or (in the longitudinal context) gene x age interaction. It can also have more power than univariate analyses to detect a quantitative trait locus influencing several traits. We apply multivariate variance components to longitudinal systolic blood pressure data from the Framingham Heart Study. We find evidence for a polygenic influence on blood pressure (heritabilities at different ages range from 27% to 38%). Tests based on a factor-analytic parameterization of the polygenic variance find significant (p < 2 x 10(-3)) evidence that different genes affect blood pressure at different ages. Still, estimates for the proportion of polygenic variance due to shared genes ran as high as 85% for some trait pairs. Univariate and multivariate linkage analyses replicate previous linkage results on chromosome 17 (maximum LOD scores of 2.2 and 2.4, respectively). In this study, multivariate analysis provides no increase in power; this is likely due to the strong positive correlation in systolic blood pressure measured at different ages.

Adult↗
PubMed2003

High concentrations of long interspersed nuclear element sequence distinguish monoallelically expressed genes.

Genes subject to monoallelic expression are expressed from only one of the two alleles either selected at random (random monoallelic genes) or in a parent-of-origin specific manner (imprinted genes). Because high densities of long interspersed nuclear element (LINE)-1 transposon sequence have been implicated in X-inactivation, we asked whether monoallelically expressed autosomal genes are also flanked by high densities of LINE-1 sequence. A statistical analysis of repeat content in the regions surrounding monoallelically and biallelically expressed genes revealed that random monoallelic genes were flanked by significantly higher densities of LINE-1 sequence, evolutionarily more recent and less truncated LINE-1 elements, fewer CpG islands, and fewer base-pairs of short interspersed nuclear elements (SINEs) sequence than biallelically expressed genes. Random monoallelic and imprinted genes were pooled and subjected to a clustering analysis algorithm, which found two clusters on the basis of aforementioned sequence characteristics. Interestingly, these clusters did not follow the random monoallelic vs. imprinted classifications. We infer that chromosomal sequence context plays a role in monoallelic gene expression and may involve the recognition of long repeats or other features. The sequence characteristics that distinguished the high-LINE-1 category were used to identify more than 1,000 additional genes from the human and mouse genomes as candidate genes for monoallelic expression.

Algorithms↗
PubMed2003

A family-based test for correlation between gene expression and trait values.

Advances in microarray technology have made it attractive to combine information on clinical traits, marker genotypes, and comprehensive gene expression from family studies to dissect complex disease genetics. Without accounting for family structure, methods that test for association between a trait and gene-expression levels can be misleading. We demonstrate that the standard unstratified test based on Pearson's correlation coefficient can produce spurious results when applied to family data, and we present a stratified family expression association test (FEXAT). We illustrate the utility of the FEXAT via simulation and an application to gene-expression data from lymphoblastoid cell lines from four CEPH families. The FEXAT has a smaller estimated false-discovery rate than the standard test when within-family correlations are of interest, and it detects biologically plausible correlations between beta catenin and genes in the WNT-activation pathway in humans that the standard test does not.

Adenomatous Polyposis Coli Protein↗
PubMed2003

Group 6: Pleiotropy and multivariate analysis.

Analysis techniques using data on several traits simultaneously allow researchers to dissect the genetic architecture affecting correlated traits, and can increase the power to detect pleiotropic genes, i.e., genes that influence two or more traits. Several of the papers in this group from Genetic Analysis Workshop 13 presented promising univariate summaries of multiple traits that detected linkage signals that standard single-trait univariate methods did not. Other papers found linkage signals using multivariate techniques that univariate techniques missed, although this was not uniformly the case. Some papers also considered the correlation among measurements of a single trait taken at different ages to assess whether the genetic architecture of the trait changed over age. Applications of the Framingham Heart Study data identified major loci jointly influencing body mass index and high-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, total cholesterol and triglycerides, and various combinations of four traits involved in metabolic syndrome.

Cardiovascular Diseases↗