Lung cancer susceptibility locus at 5p15.33

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.     

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.     

Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1?3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.     

Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.     

Genome-wide association study of quantitative resistance to southern leaf blight in the maize nested association mapping population

Nested association mapping (NAM) offers power to resolve complex, quantitative traits to their causal loci. The maize NAM population, consisting of 5,000 recombinant inbred lines (RILs) from 25 families representing the global diversity of maize, was evaluated for resistance to southern leaf blight (SLB) disease. Joint-linkage analysis identified 32 quantitative trait loci (QTLs) with predominantly small, additive effects on SLB resistance. Genome-wide association tests of maize HapMap SNPs were conducted by imputing founder SNP genotypes onto the NAM RILs. SNPs both within and outside of QTL intervals were associated with variation for SLB resistance. Many of these SNPs were within or near sequences homologous to genes previously shown to be involved in plant disease resistance. Limited linkage disequilibrium was observed around some SNPs associated with SLB resistance, indicating that the maize NAM population enables high-resolution mapping of some genome regions.     

Prairie dog colony attributes and associated vertebrate species

A survey of colony attributes and associated vertebrates on black - tail ( Cynomys ludovicianus ), Gunnison's ( C. gunnisoni ), and white - tail ( C. leucurus ) prairie dogs was made. A belt transect 1.6 km wide and 13,334 km long from Hobbs, New Mexico, to the Utah - Wyoming state line was surveyed. There were 47 colonies located (4760 ha comprising 2.2 percent) in the belt. Intercolony distances varied significantly. Three black - tail towns averaged 33 ha in area (SD = 26, range 10 &ndash; 61), II Gunnison's averaged 46 ha (SD = 43, range 16 &ndash; 150), and 33 white - tail towns averaged 125 ha (SD = 200, range 0.2 &ndash; 958). Badger activity was positively and significantly correlated to colony size and number of burrow openings on Gunnison's and white - tail towns. There were 107 vertebrate species and subspecies (one amphibian, 25 reptiles, 51 birds, 30 mammals) observed on prairie dog colonies. Results of our surveys are compared with prairie dog studies elsewhere. The role of prairie dogs and relationships to some vertebrates species are discussed.     

Carbon isotope discrimination and water relations of oak hybrid populations in southwestern Utah

The evergreen oak Quercus turbinella and the deciduous Q. gambelii form natural hybrids in southwestern Utah and northern Arizona. Hybrid individuals also are found in northern Utah in a region where only Q. gambelii currently exists, indicating that Q. turbinella has recently retreated southward. Our objectives were to (1) examine the ecophysiology of parental taxa and hybrids under natural conditions in southeastern Utah, and (2) investigate the level of integration between leaf carbon isotope discrimination (a synthetic gas exchange trait) and structural and chemical traits of leaves in morphologically variable hybrid populations. Leaf length, width, mass-to-area ratio (LMA, g m -2 ), and nitrogen concentration (N, g g -1 ) within 2 hybrid populations near New Harmony, Utah, were highly intercorrelated. Variation within the hybrid populations spanned mean values for these traits observed in parental taxa from adjacent ""pure"" populations of each species. Carbon isotope discrimination (Δ), an integrated measure of the ratio of intercellular to ambient CO 2 concentration, ranged from 16.1‰ to 19.6‰ within the 2 hybrid populations and was positively correlated with leaf nitrogen concentration and negatively correlated with LMA; individuals in hybrid populations with leaves resembling Q. gambelii had the highest leaf Δ and N concentrations and lowest LMA compared with leaves from plants that resembled Q. turbinella . CO 2 uptake is limited by stomatal conductance and possibly by mesophyll resistance to a greater extent in Q. turbinella phenotypes than in intermediate or Q. gambelii phenotypes. δD of stem xylem water (an indication of active rooting depth) and predawn water potential during the peak monsoon period in August were not correlated to leaf Δ values within the hybrid populations. Several individuals that were morphologically similar to Q. turbinella in the hybrid populations maintained high predawn water potentials and derived moisture from winter recharge that presumably was taken from deep soil layers. Apparently, a few adult individuals of the Q. turbinella phenotype in hybrid populations accessed water from deep in the soil profile, which enabled them to avoid summer drought. Reduced monsoonal activity may have been an important, but not the single, determinant of Q. turbinella s retreat from northern Utah during the recent Holocene.     

Energy and protein content of coyote prey in southeastern Idaho

Gross energy, digestible energy, crude protein, and digestible crude protein were estimated for two leporids and five rodents that were the primary prey of coyotes ( Canis latrans ) in southeastern Idaho. Digestible protein estimates differed (38%&ndash;54%) more than digestible energy (3.5&ndash;4.4 kcal), in the prey examined.     

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.     

Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure

Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes.