Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetics and Population History of Caucasus Populations

We describe aspects of genetic diversity in several ethnic popu- lations of the Caucasus Mountains of Daghestan using mitochondrial DNA sequences and a sample of 100 polymorphic Alu insertion loci. The mito- chondrial DNA (mtDNA) sequences are like those of Europe. Principal coor- dinates and nearest neighbor statistics show that there is little detectable structure in the distances among populations computed from mtDNA. The Alu frequencies of the Caucasus populations suggest that they have under- gone more genetic drift than most other groups since the dispersal of modern humans. Genetic differences among these populations are not large; instead, they are of the same order as distances among populations of Europe. We compare two methods of inference about the demography of ancient coloniz- ing populations from Africa, one based on conventional FST statistics and one based on mean Alu insertion frequencies. The two approaches agree reason- ably well if we assume that there was demographic growth in Africa before the diaspora of ancestors of contemporary regional human groups outside Africa

A dual compression system: Preliminary clinical insights from the US

There is growing evidence on an interconnection between the venous and lymphatic systems in venous leg ulceration, and the possible effects of prolonged oedema and lymphatic impairment in delayed wound healing. Compression therapy is a widely accepted treatment for venous and lymphatic disorders, as it decreases recurrence rates and prolongs the interval between recurrences. Compression bandages improve venous return, increase the volume and rate of venous flow, reduce oedema and stimulate anti-inflammatory processes. The pressure at the interface (IP) of the bandage and the skin is related to the elastic recoil of the product used and its resistance to expansion. The pressure difference between the IP in the supine and standing positions is called the static stiffness index (SSI). Elastic materials provide little resistance to muscle expansion during physical activity, resulting in small pressure differences between resting and activity, with an SSI \u3c10mmHg. Stiff, inelastic materials with a stretch of \u3c100% resist the increase of muscle volume during physical activity, producing higher peak pressures, an SSI of \u3e10mmHg and a greater haemodynamic benefit than elastic systems. UrgoK2 is a novel dual-layer high-compression system consisting of an inelastic (short stretch) and elastic (long stretch) bandage, resulting in sustained tolerable resting pressure and elevated working pressures over extended wear times. It is indicated for the treatment of active venous leg ulcers and the reduction of chronic venous oedema. Each bandage layer has a visual aid to enable application at the correct pressure level. Published European studies have assessed this compression system, exploring its consistency of application, tolerability and efficacy. This article presents the first reports of health professionals\u27 clinical experience of using the compression system in the US, where it has been recently launched. Initial feedback is promising

Human Population Genetic Structure and Inference of Group Membership

A major goal of biomedical research is to develop the capability to provide highly personalized health care. To do so, it is necessary to understand the distribution of interindividual genetic variation at loci underlying physical characteristics, disease susceptibility, and response to treatment. Variation at these loci commonly exhibits geographic structuring and may contribute to phenotypic differences between groups. Thus, in some situations, it may be important to consider these groups separately. Membership in these groups is commonly inferred by use of a proxy such as place-of-origin or ethnic affiliation. These inferences are frequently weakened, however, by use of surrogates, such as skin color, for these proxies, the distribution of which bears little resemblance to the distribution of neutral genetic variation. Consequently, it has become increasingly controversial whether proxies are sufficient and accurate representations of groups inferred from neutral genetic variation. This raises three questions: how many data are required to identify population structure at a meaningful level of resolution, to what level can population structure be resolved, and do some proxies represent population structure accurately? We assayed 100 Alu insertion polymorphisms in a heterogeneous collection of ∼565 individuals, ∼200 of whom were also typed for 60 microsatellites. Stripped of identifying information, correct assignment to the continent of origin (Africa, Asia, or Europe) with a mean accuracy of at least 90% required a minimum of 60 Alu markers or microsatellites and reached 99%–100% when ⩾100 loci were used. Less accurate assignment (87%) to the appropriate genetic cluster was possible for a historically admixed sample from southern India. These results set a minimum for the number of markers that must be tested to make strong inferences about detecting population structure among Old World populations under ideal experimental conditions. We note that, whereas some proxies correspond crudely, if at all, to population structure, the heuristic value of others is much higher. This suggests that a more flexible framework is needed for making inferences about population structure and the utility of proxies

ORIGINAL INVESTIGATION Directional migration in the Hindu castes: inferences from mitochondrial, autosomal and Y-chromosomal data

Abstract Genetic, ethnographic, and historical evidence suggests that the Hindu castes have been highly endogamous for several thousand years and that, when movement between castes does occur, it typically consists of females joining castes of higher social status. However, little is known about migration rates in these populations or the extent to which migration occurs between caste groups of low, middle, and high social status. To investigate these aspects of migration, we analyzed the largest collection of genetic markers collected to date in Hindu caste populations. These data included 45 newly typed autosomal short tandem repeat polymorphisms (STRPs), 411 bp of mitochondrial DNA sequence, and 43 Y-chromosomal single-nucleotide polymorphisms that were assayed in more than 200 individuals of known caste status sampled in Andrah Pradesh, in South India. Application of recently developed likelihood-based analyses to this dataset enabled us to obtain genetically derived estimates of intercaste migration rates. STRPs indicated migration rates of 1-2% per generation between high-, middle-, and low-status caste groups. We also found support for the hypothesis that rates of gene flow differ between maternally and paternally inherited genes. Migration rates were substantially higher in maternally than in paternally inherited markers. In addition, while prevailing patterns of migration involved movement between castes of similar rank, paternally inherited markers in the low-status castes were most likely to move into high-status castes. Our findings support earlier evidence that the caste system has been a significant, longterm source of population structuring in South Indian Hindu populations, and that patterns of migration differ between males and females

Time and sample site dependency of the optimized CO-rebreathing method

Purpose: A new method to estimate hemoglobin mass (Hbmass) requires capillary blood and rebreathing a carbon-monoxide (CO) bolus for 2 min. We hypothesized that incomplete circulatory mixing of CO could confound this method, so we compared capillary with venous blood to determine whether sampling site altered the percentage of carboxyhemoglobin (%HbCO) and the reliability and accuracy of the "2-min Hbmass." The conventional 20-min CO-rebreathing procedure was used as the Hbmass criterion. Methods: In the first experiment (N = 12), both fingertip capillary and antecubital venous blood were sampled 4 and 6 min after commencing 2 min of CO-rebreathing. Within 8 d, these subjects completed two 2-min and one 20-min CO-rebreathing periods. For the latter, capillary and venous blood were collected simultaneously after two 10-min periods of rebreathing. In a second experiment (N = 6), both capillary and venous blood were sampled 4, 6, 8, 10, and 12 min after commencing 2 min of CO-rebreathing. A third experiment (N = 6) evaluated the reliability of a modified 2-min CO-rebreathing test with capillary blood sampled at minutes 8 and 10. Results: Typical error (TE) for the first two 2-min tests was 1.1% (90% confidence limits 0.9-1.8%), but the average Hbmass from 2-min capillary blood was 4.8% lower than from venous blood for the 20-min procedure. In the second experiment, peak venous %HbCO occurred at minute 6, and the difference between capillary and venous values was minimal (mean ± SD; 0.08 ± 0.07, 0.01 ± 0.09) at minutes 8 and 10. TE for the third experiment was 1.2% (0.8-2.5%). Conclusion: A modified 2-min CO-rebreathing procedure using capillary or venous blood sampled 8 and 10 min after starting CO-rebreathing allows complete circulatory mixing and provides an accurate and reliable estimate of Hbmass.Gore CJ, Bourdon PC, Woolford SM, Ostler LM, Eastwood A and Scroop GC.http://www.ncbi.nlm.nih.gov/pubmed/1677556

DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis

Epigenetic changes are among the most common alterations observed in cancer cells, yet the mechanism by which cancer cells acquire and maintain abnormal DNA methylation patterns is not understood. Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins, some of which lack the C-terminal catalytic domain. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo , we constructed two lines of transgenic mice expressing DNMT3B7 , a truncated DNMT3B isoform commonly found in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b -deficient animals, but rarely develop cancer. However, when DNMT3B7 transgenic are bred with Eμ-Myc transgenic mice, which model aggressive B cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Eμ-Myc animals. Eμ-Myc/DNMT3B7 mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to Eμ-Myc lymphomas. These data represent the first in vivo modeling of cancer-associated DNA methylation changes and suggest that truncated DNMT3B isoforms contribute to the re-distribution of DNA methylation characterizing virtually every human tumor

Genetic Variation Among World Populations: Inferences From 100 Alu Insertion Polymorphisms

We examine the distribution and structure of human genetic diversity for 710 individuals representing 31 populations from Africa, East Asia, Europe, and India using 100 Alu insertion polymorphisms from all 22 autosomes. Alu diversity is highest in Africans (0.349) and lowest in Europeans (0.297). Alu insertion frequency is lowest in Africans (0.463) and higher in Indians (0.544), E. Asians (0.557), and Europeans (0.559). Large genetic distances are observed among African populations and between African and non-African populations. The root of a neighbor-joining network is located closest to the African populations. These findings are consistent with an African origin of modern humans and with a bottleneck effect in the human populations that left Africa to colonize the rest of the world. Genetic distances among all pairs of populations show a significant product-moment correlation with geographic distances (r = 0.69, P < 0.00001). F(ST), the proportion of genetic diversity attributable to population subdivision is 0.141 for Africans/E. Asians/Europeans, 0.047 for E. Asians/Indians/Europeans, and 0.090 for all 31 populations. Resampling analyses show that ∼50 Alu polymorphisms are sufficient to obtain accurate and reliable genetic distance estimates. These analyses also demonstrate that markers with higher F(ST) values have greater resolving power and produce more consistent genetic distance estimates