Genetic variation in cell death genes and risk of non-Hodgkin lymphoma

Background

Non-Hodgkin lymphomas are a heterogeneous group of solid tumours that constitute the 5^th highest cause of cancer mortality in the United States and Canada. Poor control of cell death in lymphocytes can lead to autoimmune disease or cancer, making genes involved in programmed cell death of lymphocytes logical candidate genes for lymphoma susceptibility.

Materials and Methods

We tested for genetic association with NHL and NHL subtypes, of SNPs in lymphocyte cell death genes using an established population-based study. 17 candidate genes were chosen based on biological function, with 123 SNPs tested. These included tagSNPs from HapMap and novel SNPs discovered by re-sequencing 47 cases in genes for which SNP representation was judged to be low. The main analysis, which estimated odds ratios by fitting data to an additive logistic regression model, used European ancestry samples that passed quality control measures (569 cases and 547 controls). A two-tiered approach for multiple testing correction was used: correction for number of tests within each gene by permutation-based methodology, followed by correction for the number of genes tested using the false discovery rate.

Results

Variant rs928883, near miR-155, showed an association (OR per A-allele: 2.80 [95% CI: 1.63–4.82]; p_F = 0.027) with marginal zone lymphoma that is significant after correction for multiple testing.

Conclusions

This is the first reported association between a germline polymorphism at a miRNA locus and lymphoma.     

An incipient invasion of brown anole lizards (<Emphasis Type="Italic">Anolis sagrei</Emphasis>) into their own native range in the Cayman Islands: a case of cryptic back-introduction

Human-mediated dispersal has reshaped distribution patterns and biogeographic relationships for many taxa. Long-distance and over-water dispersal were historically rare events for most species, but now human activities can move organisms quickly over long distances to new places. A potential consequence of human-mediated dispersal is the eventual reintroduction of individuals from an invasive population back into their native range; a dimension of biological invasion termed “cryptic back-introduction.” We investigated whether this phenomenon was occurring in the Cayman Islands where brown anole lizards (Anolis sagrei) with red dewlaps (i.e., throat fans), either native to Little Cayman or invasive on Grand Cayman, have been found on Cayman Brac where the native A. sagrei have yellow dewlaps. Our analysis of microsatellite data shows strong population-genetic structure among the three Cayman Islands, but also evidence for non-equilibrium. We found some instances of intermediate multilocus genotypes (possibly 3–9% of individuals), particularly between Grand Cayman and Cayman Brac. Furthermore, analysis of dewlap reflectance data classified six males sampled on Cayman Brac as having red dewlaps similar to lizards from Grand Cayman and Little Cayman. Lastly, one individual from Cayman Brac had an intermediate microsatellite genotype, a red dewlap, and a mtDNA haplotype from Grand Cayman. This mismatch among genetic and phenotypic data strongly suggests that invasive A. sagrei from Grand Cayman are interbreeding with native A. sagrei on Cayman Brac. To our knowledge, this is the first evidence of cryptic back-introduction. Although we demonstrate this phenomenon is occurring in the Cayman Islands, assessing its frequency there and prevalence in other systems may prove difficult due to the need for genetic data in most instances. Cryptic back-introductions may eventually provide some insight into how lineages are changed by the invasion process and may be an underappreciated way in which invasive species impact native biodiversity.     

Human mitochondrial DNA types in Finland

Summary Variation in mitochondrial DNA (mtDNA) in a sample of 110 Finns was analyzed with six restriction enzymes, AvaII, BamHI, HaeII, HinII, HpaI, and MspI, by using total blood cell DNA probed with mouse mtDNA. Two new enzyme morphs were observed, one for HaeII and one for HindII. Double-digestion experiments indicated that the BamHI morphs 2 and 3 result from base changes leading to AvaII morphs 3 and 9, respectively. Of the ten different mtDNA types observed, defined by restriction fragment patterns, seven have been previously described in Caucasoid populations. The three new Finnish mtDNA types can be derived from Caucasoid lineages by single restriction site changes. The results were used to reconstruct a phylogenetic tree for Caucasoid mtDNA types defined by the enzymes used. The frequencies of mtDNA types were used to compute genetic distances between Finns, Italians, and Israeli Jews. The frequencies of both enzyme morphs and mtDNA types show that the Finnish population is highly homogeneous.     

The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration

BACKGROUND AND AIMS: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western World. It is now evident that both genetic and environmental factors contribute to disease susceptibility. We tested the hypotheses that (a) a common coding SNP in the LOC387715 gene is associated with advanced AMD (geographic atrophy or choroidal neovascularization), and (b) that modifiable environmental exposures alter AMD susceptibility associated with this SNP. METHODS: A case-control association analysis was performed on participants (530 advanced AMD cases and 280 controls) ascertained as part of the multi-center Age-Related Eye Disease Study. AMD status was determined by the reading center from fundus photographs using the AREDS AMD grading categorization. Environmental risk factor exposure data was collected from participants whose DNA was also genotyped for the LOC387715 gene SNP rs10490924. Multivariate logistic regression analyses were performed. RESULTS AND CONCLUSIONS: The number of risk alleles at the LOC387715 SNP was associated with advanced AMD, with odds ratios (OR) = 3.0 (95% confidence interval (CI) 2.1-4.3) for the GT heterozygous genotype and OR = 12.1 (5.6-26.5) for the homozygous TT risk genotype, after controlling for demographic and behavioral risk factors. The LOC387715 SNP was associated with both forms of advanced AMD. Current cigarette smoking and body mass index were independently related to AMD, controlling for genotype. However, there was no statistical interaction between LOC387715 genotype and smoking with regard to advanced AMD development.     

X-ray microanalysis of apical fluid in cystic fibrosis airway epithelial cell lines.

The ionic composition of the fluid lining the airways (airway surface liquid, ASL) in healthy subjects and patients with cystic fibrosis (CF) has been a matter of controversy. It has been attempted to resolve conflicting theories by using cell cultures, but published results show a wide variety of values for the ionic concentrations in the apical fluid in these cultures. To investigate CFTR-mediated HCO(3)(-) conductance and the role of HCO(3)(-) in regulating ASL pH we determined the pH of the fluid covering the apical surface of airway epithelial cells. A normal (16HBE14o (-)) and a CF (CFBE41o (-)) bronchial epithelial cell line were grown on membrane inserts in both a liquid-liquid interface culture system for 7 days, and in an air-liquid interface culture system for one month. The elemental composition of the fluid covering the apical surface was determined by X-ray microanalysis of frozen-hydrated specimens, or by X-ray microanalysis of Sephadex beads that had been equilibrated with the apical fluid. Analysis showed that the apical fluid had a Na(+) and Cl(-) concentration of about 80-100 mM and thus was slightly hypotonic. The ionic concentrations were somewhat higher in air-liquid interface than in liquid-liquid interface cultures. The apical fluid in CF cells had significantly higher concentrations of Na and Cl than that in control cultures. In control cultures, the concentrations of Na and Cl in the apical fluid increased if glibenclamide, an inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR) was added to the apical medium. Exposing the cells to the metabolic inhibitor NaCN also resulted in a significant increase of the Na and Cl concentrations in the apical fluid. The results agree with the notion that these cell cultures are mainly absorptive cells, and that ion absorption by the CF cells is reduced compared to that in normal cells. The pH measurements of the fluid covering the apical part of cell cultures support the notion that bicarbonate ions may be transported by CFTR, and that this can be inhibited by specific CFTR inhibitors.     

DNA content as a prognostic marker of oral lichen planus with a risk of cancer development

OBJECTIVE: To assess the presence of aneuploidy in oral lichen planus (OLP) and its usefulness as a prognostic marker. STUDY DESIGN: Eighty-one formalin-fixed, paraffin-embedded biopsy samples taken from atrophic-erosive OLP from 70 patients were studied. Approximately 150 random nuclei in basal and/or parabasal epithelia were analyzed with static cytometry. RESULTS: Aneuploidy was detected in 41% of samples. OLPs with ulcerations or location in the tongue had significantly higher values, respectively, for the 2.5c exceeding rate (ER) (p<0.001 and 0.001) and proliferation index (PI) (p = 0.012 and 0.013) than did lesions without ulcerations or at other locations. 2.5c ER was significantly higher in dysplastic OLP lesions (p < 0.001), and the significant value (p = 0.001)for 2.5c ER discriminating DNA aneuploidy was 15.3%. In multivariate analysis only the G2/M ER (G2/MER) was a significant independent predictor of developing cancer in OLP (OR 2.349, 95% CI 1.39-3.97, p = 0.001). CONCLUSION: Ulcerated atrophic-erosive OLPs of the tongue and with dysplasia are at increased risk of cancer development. 2.5c ER, PI and G2/MER might be useful in prognosticating the increased risk of malignancy in OLP.     

Biodiversity effects on productivity and stability of marine macroalgal communities: the role of environmental context

The influence of biodiversity on ecosystem functioning has been the focus of much recent research, but the role of environmental context and the mechanisms by which it may influence diversity effects on production and stability remain poorly understood. We assembled marine macroalgal communities in two mesocosm experiments that varied nutrient supply, and at four field sites that differed naturally in environmental conditions. Concordant with theory, nutrient addition promoted positive species richness effects on algal growth in the first mesocosm experiment; however, it tended to weaken the positive diversity relationship found under ambient conditions in a second experiment the next year. In the field experiments, species richness increased algal biomass production at two of four sites. Together, these experiments indicate that diversity effects on algal biomass production are strongly influenced by environmental conditions that vary over space and time. In decomposing the net biodiversity effect into its component mechanisms, seven of the eight experimental settings showed positive complementarity effects (suggesting facilitation or complementary resource use) countered by negative selection effects (i.e. enhanced growth in mixture of otherwise slow growing species) to varying degrees. Under no conditions, including nutrient enrichment, did we find evidence of positive selection effects commonly thought to drive positive diversity effects. Species richness enhanced stability of algal community biomass across a range of environmental settings in our field experiments. Hence, while species richness can increase production, enhanced stability is also an important functional outcome of maintaining diverse marine macroalgal communities.     

Seasonal Viral Loop Dynamics in Two Large Ultraoligotrophic Antarctic Freshwater Lakes

The effect of viruses on the microbial loop, with particular emphasis on bacteria, was investigated over an annual cycle in 2003–2004 in Lake Druzhby and Crooked Lake, two large ultraoligotrophic freshwater lakes in the Vestfold Hills, Eastern Antarctica. Viral abundance ranged from 0.16 to 1.56 × 10⁹ particles L^-1;1 and bacterial abundances ranged from 0.10 to 0.24 × 10⁹ cells L^-1;1, with the lowest bacterial abundances noted in the winter months. Virus-to-bacteria ratios (VBR) were consistently low in both lakes throughout the season, ranging from 1.2 to 8.4. lysogenic bacteria, determined by induction with mitomycin C, were detected on three sampling occasions out of 10 in both lakes. In Lake Druzhby and Crooked Lake, lysogenic bacteria made up between 18% and 73% of the total bacteria population during the lysogenic events. Bacterial production ranged from 8.2 to 304.9 × 10⁶ cells L^-1;1 day^-1;1 and lytic viral production ranged from 47.5 to 718.4 × 10⁶ viruslike particles L^-1;1 day^-1;1. When only considering primary production, heterotrophic nanoflagellate (HNF) grazing and viral lysis as the major contributors to the DOC pool (i.e., autochthonous sources), we estimated a high contribution from viruses during the winter months when >60% of the carbon supplied to the DOC pool originated from viral lysis. In contrast, during the summer <20% originated from viral lysis. Our study shows that viral process in ultraoligotrophic Antarctic lakes may be of quantitative significance with respect to carbon flow especially during the dark winter period.     

Estimation of breed contributions to present and future genetic diversity of 44 North Eurasian cattle breeds using core set diversity measures

Extinction of breeds threatens genetic diversity of livestock species. The need to conserve genetic diversity is widely accepted but involves in general two questions: (i) is the expected loss of diversity in a set of breeds within a defined future time horizon large enough to establish a conservation plan, and if so (ii) which breeds should be prioritised for such a conservation plan? The present study uses a marker assisted methodology to address these questions. The methodology combines core set diversity measures with a stochastic method for the estimation of expected future diversity and breed marginal diversities. The latter is defined as the change in the total diversity of all breeds caused by a one unit decrease in extinction probability of a particular breed. The stochastic method was validated by means of simulations. A large field data set consisting of 44 North Eurasian cattle breeds was analysed using simplified determined extinction probabilities. The results show that the expected loss of diversity in this set within the next 20 to 50 years is between 1 and 3% of the actual diversity, provided that the extinction probabilities which were used are approximately valid. If this loss is to be reduced, it is sufficient to include those three to five breeds with the highest marginal diversity in a conservation scheme.