A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.     

Forecasting non-normal time series

We look at the problem of forecasting time series which are not normally distributed. An overall approach is suggested which works both on simulated data and on real data sets. The idea is intuitively attractive and has the considerable advantage that it can readily be understood by non-specialists. Our approach is based on ARMA methodology and our models are estimated via a likelihood procedure which takes into account the non-normality of the data. We examine in some detail the circumstances in which taking explicit account of the nonnormality improves the forecasting process in a significant way. Results from several simulated and real series are included.     

Specific expression of an elastase-human growth hormone fusion gene in pancreatic acinar cells of transgenic mice

Transfection of genes into tissue culture cell lines has demonstrated that relatively short DNA sequences can allow expression of immunoglobulin, insulin and chymotrypsin genes in their appropriate cell types. A definitive test of cell-specific gene expression, however, requires testing genes in every possible cell type, an experiment performed easily by introducing the gene in question into the germ line of an animal. Transfer of intact genes into mice has demonstrated that a mouse immunoglobulin kappa gene is expressed specifically in B lymphocytes, a rat elastase I gene is expressed specifically in pancreas and a chicken transferrin gene is expressed preferentially in liver. Mouse metallothionein-growth hormone fusion genes introduced into mice are preferentially expressed in the liver, consistent with the expression of endogenous metallothionein genes, but initial experiments with beta-globin genes have not revealed proper regulation. To identify the DNA elements required for pancreas-specific expression of the rat elastase I gene, we joined the 5'-flanking region of this gene to the human growth hormone (hGH) structural gene and introduced the fusion gene into mice. Here we demonstrate that a fusion gene containing only 213 base pairs (bp) of elastase I gene sequence directs expression of hGH in pancreatic acinar cells.     

A non-spherical core in the explosion of supernova SN 2004dj

An important and perhaps critical clue to the mechanism driving the explosion of massive stars as supernovae is provided by the accumulating evidence for asymmetry in the explosion. Indirect evidence comes from high pulsar velocities, associations of supernovae with long-soft gamma-ray bursts, and asymmetries in late-time emission-line profiles. Spectropolarimetry provides a direct probe of young supernova geometry, with higher polarization generally indicating a greater departure from spherical symmetry. Large polarizations have been measured for 'stripped-envelope' (that is, type Ic; ref. 7) supernovae, which confirms their non-spherical morphology; but the explosions of massive stars with intact hydrogen envelopes (type II-P supernovae) have shown only weak polarizations at the early times observed. Here we report multi-epoch spectropolarimetry of a classic type II-P supernova that reveals the abrupt appearance of significant polarization when the inner core is first exposed in the thinning ejecta (approximately 90 days after explosion). We infer a departure from spherical symmetry of at least 30 per cent for the inner ejecta. Combined with earlier results, this suggests that a strongly non-spherical explosion may be a generic feature of core-collapse supernovae of all types, where the asphericity in type II-P supernovae is cloaked at early times by the massive, opaque, hydrogen envelope.     

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.     

Mice heterozygous for mutation in Atm,the gene involved in ataxia-telangiectasia,have heightened susceptibility to cancer

Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers. We demonstrate here that Atm 'knock-in' (Atm-Delta SRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm(+/-)) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.     

Modeling and forecasting time series with a general non-normal distribution

We propose a model for time series with a general marginal distribution given by the Johnson family of distributions. We investigate for which Johnson distributions forecasting using the model is likely to be most effective compared to using a linear model. Monte Carlo simulation is used to assess the reliability of methods for determining which of the three Johnson forms is most appropriate for a given series. Finally, we give model fitting and forecasting results using the modeling procedure on a selection of simulated and real time series.