Ischemic stroke risk, smoking, and the genetics of inflammation in a biracial population: the stroke prevention in young women study

<p>Abstract</p> <p>Background</p> <p>Although cigarette smoking is a well-established risk factor for vascular disease, the genetic mechanisms that link cigarette smoking to an increased incidence of stroke are not well understood. Genetic variations within the genes of the inflammatory pathways are thought to partially mediate this risk. Here we evaluate the association of several inflammatory gene single nucleotide polymorphisms (SNPs) with ischemic stroke risk among young women, further stratified by current cigarette smoking status.</p> <p>Methods</p> <p>A population-based case-control study of stroke among women aged 15–49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-comparable control subjects (43.1% African-American). Several inflammatory candidate gene SNPs chosen through literature review were genotyped in the study population and assessed for association with stroke and interaction with smoking status.</p> <p>Results</p> <p>Of the 8 SNPs (across 6 genes) analyzed, only <it>IL6 </it>SNP rs2069832 (allele C, African-American frequency = 92%, Caucasian frequency = 55%) was found to be significantly associated with stroke using an additive model, and this was only among African-Americans (age-adjusted: OR = 2.2, 95% CI = 1.0–5.0, p = 0.049; risk factor adjusted: OR = 2.5, 95% CI = 1.0–6.5, p = 0.05). When stratified by smoking status, two SNPs demonstrated statistically significant gene-environment interactions. First, the T allele (frequency = 5%) of <it>IL6 </it>SNP rs2069830 was found to be protective among non-smokers (OR = 0.30, 95% CI = 0.11–.082, p = 0.02), but not among smokers (OR = 1.63, 95% CI = 0.48–5.58, p = 0.43); genotype by smoking interaction (p = 0.036). Second, the C allele (frequency = 39%) of <it>CD14 </it>SNP rs2569190 was found to increase risk among smokers (OR = 2.05, 95% CI = 1.09–3.86, p = 0.03), but not among non-smokers (OR = 0.93, 95% CI = 0.62–1.39, p = 0.72); genotype by smoking interaction (p = 0.039).</p> <p>Conclusion</p> <p>This study demonstrates that inflammatory gene SNPs are associated with early-onset ischemic stroke among African-American women (<it>IL6</it>) and that cigarette smoking may modulate stroke risk through a gene-environment interaction (<it>IL6 and CD14</it>). Our finding replicates a prior study showing an interaction with smoking and the C allele of <it>CD14 </it>SNP rs2569190.</p

Extreme oxygen isotope zoning in garnet and zircon from a metachert block in melange reveals metasomatism at the peak of subduction metamorphism

A tectonic block of garnet quartzite in the amphibolite-facies melange of the Catalina Schist (Santa Catalina Island, California, USA) records the metasomatic pre-treatment of high-delta O-18 sediments as they enter the subduction zone. The block is primarily quartz, but contains two generations of garnet that record extreme oxygen isotope disequilibrium and inverse fractionations between garnet cores and matrix quartz. Rare millimeter-scale garnet crystals record prograde cation zoning patterns, whereas more abundant similar to 200-mu m-diameter crystals have the same composition as rims on the larger garnets. Garnets of both generations have high-delta O-18 cores (20.8 parts per thousand-26.3 parts per thousand, Vienna standard mean ocean water) that require an unusually high-delta O-18 protolith and lower-delta O-18, less variable rims (10.0 parts per thousand-11.2 parts per thousand). Matrix quartz values are homogeneous (13.6 parts per thousand). Zircon crystals contain detrital cores (delta O-18 = 4.7 parts per thousand-8.5 parts per thousand, 124.6 + 1.4/-2.9 Ma) with a characteristic igneous trace element composition likely sourced from arc volcanics, surrounded by zircon with metamorphic age (115.1 +/- 2.5 Ma) and trace element compositions that suggest growth in the presence of garnet. Metamorphic zircon decreases in delta O-18 from near-core (24.1 parts per thousand) to rim (12.4 parts per thousand), in equilibrium with zoned garnets. Collectively, the data document the subduction of a mixed high-delta O-18 siliceous ooze and/or volcanic ash protolith reaching temperatures of 550-625 degrees C prior to the nucleation of small garnets without influence from external fluids. Metasomatism was recorded in rims of both garnet and zircon populations as large volumes of broadly homogeneous subduction fluids stripped matrix quartz of its extremely high oxygen isotope signature. Thus, zoned garnet and zircon in high-delta O-18 subducted sediments offer a detailed window into subduction fluids

Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women

Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = −0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery

Assessing Theoretical Conclusions With Blinded Inference to Investigate a Potential Inference Crisis

Scientific advances across a range of disciplines hinge on the ability to make inferences about unobservable theoretical entities on the basis of empirical data patterns. Accurate inferences rely on both discovering valid, replicable data patterns and accurately interpreting those patterns in terms of their implications for theoretical constructs. The replication crisis in science has led to widespread efforts to improve the reliability of research findings, but comparatively little attention has been devoted to the validity of inferences based on those findings. Using an example from cognitive psychology, we demonstrate a blinded-inference paradigm for assessing the quality of theoretical inferences from data. Our results reveal substantial variability in experts’ judgments on the very same data, hinting at a possible inference crisis

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Extreme oxygen isotope zoning in garnet and zircon from a metachert block in mélange reveals metasomatism at the peak of subduction metamorphism

A tectonic block of garnet quartzite in the amphibolite-facies mélange of the Catalina Schist (Santa Catalina Island, California, USA) records the metasomatic pre-treatment of high-δ18O sediments as they enter the subduction zone. The block is primarily quartz, but contains two generations of garnet that record extreme oxygen isotope disequilibrium and inverse fractionations between garnet cores and matrix quartz. Rare millimeter-scale garnet crystals record prograde cation zoning patterns, whereas more abundant ∼200-μm-diameter crystals have the same composition as rims on the larger garnets. Garnets of both generations have high-δ18O cores (20.8‰–26.3‰, Vienna standard mean ocean water) that require an unusually high-δ18O protolith and lower-δ18O, less variable rims (10.0‰–11.2‰). Matrix quartz values are homogeneous (13.6‰). Zircon crystals contain detrital cores (δ18O = 4.7‰–8.5‰, 124.6 +1.4/−2.9 Ma) with a characteristic igneous trace element composition likely sourced from arc volcanics, surrounded by zircon with metamorphic age (115.1 ± 2.5 Ma) and trace element compositions that suggest growth in the presence of garnet. Metamorphic zircon decreases in δ18O from near-core (24.1‰) to rim (12.4‰), in equilibrium with zoned garnets. Collectively, the data document the subduction of a mixed high-δ18O siliceous ooze and/or volcanic ash protolith reaching temperatures of 550–625 °C prior to the nucleation of small garnets without influence from external fluids. Metasomatism was recorded in rims of both garnet and zircon populations as large volumes of broadly homogeneous subduction fluids stripped matrix quartz of its extremely high oxygen isotope signature. Thus, zoned garnet and zircon in high-δ18O subducted sediments offer a detailed window into subduction fluids

Complete Genomic Sequence of the Virulent Salmonella Bacteriophage SP6

We report the complete genome sequence of enterobacteriophage SP6, which infects Salmonella enterica serovar Typhimurium. The genome contains 43,769 bp, including a 174-bp direct terminal repeat. The gene content and organization clearly place SP6 in the coliphage T7 group of phages, but there is ∼5 kb at the right end of the genome that is not present in other members of the group, and the homologues of T7 genes 1.3 through 3 appear to have undergone an unusual reorganization. Sequence analysis identified 10 putative promoters for the SP6-encoded RNA polymerase and seven putative rho-independent terminators. The terminator following the gene encoding the major capsid subunit has a termination efficiency of about 50% with the SP6-encoded RNA polymerase. Phylogenetic analysis of phages related to SP6 provided clear evidence for horizontal exchange of sequences in the ancestry of these phages and clearly demarcated exchange boundaries; one of the recombination joints lies within the coding region for a phage exonuclease. Bioinformatic analysis of the SP6 sequence strongly suggested that DNA replication occurs in large part through a bidirectional mechanism, possibly with circular intermediates