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PubMed1992

High blood pressure: hunting the genes.

High blood pressure is a disease of unknown cause. Family history of the disease indicates higher risk, but it is not known which genes are involved or how they interact with environmental influences to produce the disorder. Molecular biology offers an approach to problems that have not so far been solved by classical physiology or biochemistry. By analysing polymorphic variation in chromosome markers such as minisatellite sequences, or by restriction fragment polymorphism analysis of candidate genes, attempts are being made to link genetic variations with hypertension. In genetically hypertensive rats, hypertension is associated with a polymorphism of the renin gene and with other loci on chromosomes 10 and 18. The role of these loci in human hypertension remains to be determined. Other genes such as sodium-lithium countertransport may be involved. Environmental factors such as stress or salt intake could influence the rate or timing of expression of certain genes and thus result in hypertension.

Adult↗
PubMed1999

Search for a gene x environment interaction: G x E hunt.

We developed a method to identify gene x environment interactions (G x Es). To test this method in the simulated data (Problem 2, GAW11), we first identified an environmental factor (E1) that was associated with the simulated disorder. We stratified affected sibling pairs (ASPs) into two groups, those concordant for the presence of E1 and those concordant for the absence of E1. We then localized genes on chromosomes 3 and 5 using identity-by-descent (IBD) sharing rates among ASPs. Because the stratified IBD sharing rates are independent of the environmental factor if there is no G x E, we inferred the existence of a G x E near loci 3G44 and 3G45 by testing whether the proportion of ASPs sharing no alleles IBD differed among the two groups.

Environment↗
PubMed1999

Hunting genetic diseases: exploring a multistage approach to identifying disease loci.

Genomic screen data for a hypothetical disease was used in a two-stage analysis to search for disease loci. We performed both trait-model-dependent and trait-model-free analyses to test their relative power. Results of our first-stage screen in 200 families suggested 13 regions for further analysis. Second-stage follow-up in another 200 families confirmed a single region on chromosome 3 near marker D3G045 with a combined lod score across all 400 families of 6.24 and a sib-pair maximum lod score (MLS) of 4.79. The MLS were highly correlated with both the autosomal dominant and autosomal recessive lod scores in all data sets, suggesting that both trait-model-dependent and trait-model-free methods can be useful for identifying candidate regions for complex disease loci. Reanalysis of the data using alternative sampling schemes suggested that sampling variation has a significant effect on locus detection.

Genetic Markers↗
PubMed2001

Should we consider gene x environment interaction in the hunt for quantitative trait loci?

We address the question of whether one can obtain increased power for finding a quantitative trait locus (QTL) if a gene x environment (G x E) interaction is incorporated directly into the linkage analysis. We consider both parametric and nonparametric analysis approaches to including G x E interaction. For the former, we utilize joint segregation and linkage analysis to estimate simultaneously the recombination fraction and a G x E interaction effect, as well as the remaining model parameters. The nonparametric approach is based on an extension of the Haseman-Elston method applied to sib pairs to include a regression of the squared trait difference on marker-identity-by-descent (IBD) probability (pi), the sibling covariate sum (z), and pi x z. We utilize 50 replicates of the simulated data and compare empirical power of the various approaches to detect MG4, a locus that is involved in a strong interaction with age for Q4 and in a weaker interaction with environmental factor E2 for Q3. Using the parametric approach, including a G x age effect does increase power for detecting linkage between MG4 and Q4 compared with ignoring the interaction (powers 58% and 38%, respectively, to exceed a lod score of 3.0). On the other hand, including a G x E2 interaction has little effect on the power to detect linkage between MG4 and Q3. The nonparametric approach leads to qualitatively similar findings. We conclude that it is beneficial to incorporate G x E interaction into a linkage analysis, provided the interaction effect is of sufficiently strong magnitude.

Chromosome Mapping↗
PubMed2006

Recreational physical activity and risk of prostate cancer: A prospective population-based study in Norway (the HUNT study).

Physical activity has been studied in relation to prostate cancer risk, but the findings have been inconclusive. We prospectively examined the association between self-reported recreational physical activity and overall risk of prostate cancer, risk of advanced disease and risk of prostate cancer death in a cohort of 29,110 Norwegian men. Incident prostate cancers were obtained from the Norwegian Cancer Registry, and prostate cancer deaths were obtained from the national Cause of Death Registry. During 17 years of follow-up, 957 incident cases were identified, 266 of them were advanced (i.e. metastases at diagnosis) and 354 of the incident cases died from prostate cancer. In multivariable analysis, frequency and duration of exercise were inversely associated with the risk of advanced prostate cancer (p for trend = 0.04 and 0.02). We computed a summary score that combined frequency, duration and intensity of exercise, and this score showed inverse associations with advanced prostate cancer risk and mortality (p for trend = 0.02 and 0.07). Compared to men who reported no activity, the relative risks (95% confidence intervals) among men in the highest category of physical exercise was 0.64 (0.43-0.95) for advanced prostate cancer and 0.67 (0.48-0.94) for prostate cancer death. We found no association between physical activity and overall risk of prostate cancer. We conclude that recreational physical exercise is associated with reduced risk of advanced prostate cancer and prostate cancer death.

Adult↗
PubMed2005

Hunting the primary: novel strategies for defining the origin of tumours.

In 1995, two methods of genome-wide expression profiling were first described: expression microarrays and serial analysis of gene expression (SAGE). In the subsequent 10 years, many hundreds of papers have been published describing the application of these technologies to a wide spectrum of biological and clinical questions. Common to all of this research is a basic process of data gathering and analysis. The techniques and statistical and bio-informatic tools involved in this process are reviewed. The processes of class discovery (using clustering and self-organizing maps), class prediction (weighted voting, k nearest neighbour, support vector machines, and artificial neural networks), target identification (fold change, discriminant analysis, and principal component analysis), and target validation (RT-PCR and tissue microarrays) are described. Finally, the diagnostic problem of adenocarcinomas that present as metastases of unknown origin is reviewed, and it is demonstrated how integration of expression profiling techniques promises to throw new light on this important clinical challenge.

Adenocarcinoma↗
PubMed2004

Use of inhaled corticosteroids and bone mineral density in a population based study: the Nord-Trøndelag Health Study (the HUNT Study).

Conflicting results have been reported of the long-term effects of treatment with inhaled corticosteroids (ICS) on bone. The objective of this study was to compare ICS users and non-users regarding bone mineral density (BMD) in a large population. A total of 65,225 adults participated in a cross-sectional study in the Nord-Trøndelag Health Study 1995-1997. Those reporting asthma or asthma-related symptoms, were invited to have bone densitometry of the forearm, flow volume spirometry and a personal interview. Altogether 4482 women and 4142 men participated, of whom 2113 reported ever use and 6511 never use of ICS. Never-users of corticosteroids had a mean BMD, adjusted for confounders (age, square age, sex, body mass index, height, physical activity, work load, packyears, family history of osteoporosis and in women number of years since menopause and use of hormone replacement therapy), of 0.493 g/cm2 at the distal site. Subjects having only used ICS or combined with courses of prednisolone, had 0.008 g/cm2 (95%CI: 0.005-0.011) lower BMD whilst users of prednisolone > or = 6 months had 0.038 g/cm2 (0.021-0.055) lower level. No dose response association between ICS and BMD, or difference in BMD by type of ICS was found. The association between CS use and BMD was independent of the measuring site. ICS use was associated with lower BMD. The lack of dose response in this study might be due to a narrow dose range or indicates that other characteristics of the patient group are contributing to the observed difference in ICS users compared to never-users.

Administration, Inhalation↗
PubMed2007

LongCriSP: a test for bump hunting in longitudinal data.

We propose an extension of the Harezlak and Heckman (J. Comput. Graph. Statist. 2001; 10(4): 713-729) test for detecting local extrema to the longitudinal data setting. We use penalized spline regression techniques (Statist. Sci. 1996; 11:89-102) to provide a computationally efficient method of testing for relatively large data sets. We estimate the p-values of our test, LongCriSP, with a smoothed bootstrap. Our simulation studies indicate that the test is generally conservative and has power exceeding 70 per cent at the alpha = 0.1 nominal level in most considered settings. Finally, we apply our testing procedure to the longitudinal measurements of body mass index of former prisoners of war in Vietnam and conclude that the mean population curve exhibits non-monotone behaviour.

Body Mass Index↗
PubMed2000

The effect of experience on the hunting success of newly emerged spiderlings.

Initial interactions with prey may affect a predator's subsequent foraging success. With experience, second-instar Misumena vatia spiderlings (Thomisidae) that had recently emerged from their egg sacs oriented faster to fruit flies (Drosophila melanogaster) than näive individuals. Orientation time of these spiderlings decreased rapidly for the first two to three runs (every third day) in a simple laboratory setting, and then remained low and relatively constant. Time to capture a fly also declined initially, but subsequently became extremely variable, increasing prior to moult. Increase in capture time and the failure to capture prey appeared associated with impending moult, rather than satiation. Spiderlings oriented to prey more rapidly at the beginning of the third instar than at the start of the second instar, suggesting that experience still enhanced performance after a moult cycle. Overall capture times at the beginning of the third instar decreased from those at the end of the second instar, but did not differ significantly from the beginning of the second instar, although spiderlings gaining the most biomass had the shortest mean capture times. In a second experiment, time to orient and time to capture prey did not differ in näive, second-instar siblings run 1 and 3 days after emergence from their egg sacs. However, 3-day individuals that had captured prey each day (confiscated before they could feed) oriented faster than näive 3-day-old siblings, but did not differ in the time taken to capture prey. Experience, rather than age or energetic condition, best explains these changes in performance. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1994

Hunt for singlet oxygen under in vivo conditions.

It is widely accepted that applying exogenous photosensitizers in living organism the photodynamic effect is mediated by singlet oxygen formed by energy transfer from excited sensitizer to oxygen present in the cells (Type II mechanism). Though in homogeneous solutions singlet oxygen was detected during sensitization, efforts to observe it in vivo failed, so far. Kinetic considerations based on the assumption that triplet sensitizer molecules interact with (doublet) free radicals accumulated in the tissue as well as on literature data indicate that the steady state concentration of singlet oxygen can decrease by more than one order of magnitude at transition from homogeneous systems to in vivo conditions making it undetectable.

Kinetics↗
PubMed1998

Gene hunting without sequencing genomic clones: finding exon boundaries in cDNAs.

We propose a new experimental protocol, ExonPCR, which is able to identify exon boundaries in a cDNA even in the absence of any genomic clones. ExonPCR can bypass the isolation, characterization, and DNA sequencing of subclones of genomic DNA to determine exon boundaries: a major effort in the process of positional cloning. Given a cDNA sequence, ExonPCR uses a series of "adaptive" steps to analyze the PCR products from cDNA and genomic DNA thereby revealing the approximate positions of "hidden" exon boundaries in the cDNA. The nucleotide sequence of adjacent intronic regions is determined by ligation-mediated PCR. Primers adjacent to the "hidden" exon boundaries are used to amplify genomic DNA followed by limited DNA sequencing of the PCR product. The method was successfully tested on the 3-kb hMSH2 cDNA with 16 known exons and the 9-kb PRDII-BF1 cDNA with a previously unknown number of exons. We subsequently developed the ExonPCR algorithm and software to direct the experimental protocol using a strategy that is analogous to that used in the game "Twenty Questions." Through the use of ExonPCR, the search for disease-causing mutations can be initiated almost immediately after cDNA clones in a genetically mapped region become available. This approach would be most valuable in gene discovery strategies that focus initially on cDNA isolation.

Animals↗
PubMed1997

Identifying the molecular control of T-cell death; on the hunt for killer genes.

Apoptosis, the series of morphological changes which result from a cell-suicide program, has fascinated biologists in recent years. Identifying apoptosis regulatory and effector genes to elucidate the molecular mechanisms of programmed cell death has been a challenging but successful endeavor. However, our knowledge of this process is far from complete. The discovery of 'death genes' has provided insight into the homeostatic mechanisms regulating the immune system including the clonal deletion of self-reactive and activated lymphocytes. Notably, apoptosis induced by T-cell receptor (TCR) stimulation is the critical event which drives negative selection of thymocytes and peripheral T cells. Differential display, differential screening and subtractive hybridization have provided the technical backbone for the isolation of genes whose expression is specific for apoptotic cells. However, the genes identified by these techniques only correlate with the apoptotic phenotype and their expression may be the result of non-apoptotic pathways also affected by the death-inducing agent. Here, we review what is known about the molecular mechanisms of TCR-triggered apoptosis and discuss techniques used to isolate and characterize death regulatory molecules. In addition, we present a novel approach utilizing somatic cell genetics to clone genes involved in TCR-triggered apoptosis.

Apoptosis↗