scholarly journals Genetic study of late-onset neonatal sepsis reveals significant differences by sex

2021 ◽  
Author(s):  
Timothy H. Ciesielski ◽  
Xueyi Zhang ◽  
Alessandra Tacconelli ◽  
Irja Lutsar ◽  
Vincent Meiffredy de Cabre ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Neonatal Sepsis ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Total Sample ◽  
Single Sex ◽  
A Genome ◽  
Threatening Condition ◽  
Life Threatening ◽  
Pathway Analyses

Late-Onset Neonatal Sepsis (LOS) is a rare, but life-threatening condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not 100% preventable, identifying susceptibility factors is critical to defining neonates at greater risk. Prior studies demonstrated that both genetics and infant sex influence susceptibility. We, therefore, performed a genome wide association study (GWAS) with 224 cases and 273 controls from six European countries to identify genetic risk factors. We tested for association with both autosomal and X-chromosome variants in the total sample and in the samples stratified by sex. In total 71 SNPs associated with neonatal sepsis at p<1x10-4 in at least one analysis. Most importantly, the sex stratified analyses revealed associations with multiple SNPs (28 SNPs in males and 16 in females), but none of 44 SNPs from single-sex analyses associated with sepsis in the other sex at p<0.05, and the vast majority showed significant SNPxsex interactions (17 of 28 from the male-only analyses and all 16 from the female-only study). Pathway analyses showed that NOTCH signaling is over-represented among loci identified by the analyses. Our results indicate that susceptibility to LOS is genetically sexually dimorphic, and suggest that NOTCH signaling is likely to play a role in it.

scholarly journals Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

2018 ◽  
Vol 109 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Dylan M Williams ◽  
Sara Hägg ◽  
Nancy L Pedersen
Keyword(s):  
Alzheimer Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Late Onset ◽  
Association Studies ◽  
Nucleotide Polymorphisms ◽  
Primary Methods ◽  
A Genome ◽  
Β Carotene

ABSTRACT Background Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation. Objectives In order to infer whether long-term circulating antioxidant exposure plays a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of 4 circulating antioxidants that are modifiable by diet. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single-nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results. Conclusions Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

scholarly journals Up-regulation of BTLA expression in myeloid dendritic cells in neonatal sepsis associated with the treatment outcome and down-regulation of DC function

2020 ◽  
Author(s):  
Wandang Wang ◽  
Xuran Yang ◽  
Mingfa Guo ◽  
Zhifeng Pan ◽  
Mingjin Qiu ◽  
...  
Keyword(s):  
Neonatal Sepsis ◽  
Myeloid Dendritic Cells ◽  
Hla Dr ◽  
Tnf Α ◽  
Threatening Condition ◽  
Duration Of Hospitalization ◽  
Inflammatory Phenotype ◽  
Life Threatening ◽  
Antigen Presenting

Abstract Background: Neonatal sepsis is an acute life-threatening condition in neonates, and a proper innate inflammatory is essential for prevention of the systemic inflammation associated with sepsis. As the most potential antigen-presenting innate immune cells, dentritic cells (DCs) dysfunction has been verified detrimental for sepsis. B and T lymphocyte attenuator (BTLA) is an immune-regulatory receptor shown to be associated with DCs dysfunction. However, the role of BTLA expression in myeloid DCs (mDCs) in neonatal sepsis is unknown. Methods: 61 of neonates with sepsis and 32 of neonates having no suspicion of sepsis as control were enrolled into this study. BTLA and HLA-DR expression in mDCs was measured by flow cytometry. To further study the role of BTLA in regulating mDCs function, BTLA+mDCs and BTLA-mDCs from septic neonates were sorted and utilized to evaluate the phagacytosis capacity, bactericidal ability as well as cytokine secretion of mDCs.Results: A higher percentage of BTLA+mDCs were observed in neonatal septic patients and the percentage was positively correlated to the duration of hospitalization of neonates as well as the severity of sepsis. Moreover, a decrease MFI expression of HLA-DR was found in mDCs in neonatal sepsis, which expression was negatively correlated with the percentage of BTLA+mDCs. When compared to BTLA-mDCs, sorted BTLA+mDCs exhibited lower FITC-dextran uptake capacity but more CFU E.coli number after cells challenged by E.coli. In addition, BTLA+mDCs comparatively secreted lower level of TNF-α and IL-12, but higher IL-10. Conclusions: A higher level of BTLA in mDCs in the observed septic neonates was associated to the severity of neonatal sepsis; therefore, BTLA expression in mDCs could be a useful biomarker help to determine the neonatal sepsis development. Additionally, BTLA negatively regulated the phagocytosis capacity and bactericidal ability of mDCs and lowered their antigen-presenting ability as well as altered cells into an anti-inflammatory phenotype. Thus, targeting BTLA in mDCs may be a new therapeutic strategy for neonatal sepsis.

scholarly journals A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

2008 ◽  
Vol 1 (1) ◽  
Author(s):  
Richard Abraham ◽  
Valentina Moskvina ◽  
Rebecca Sims ◽  
Paul Hollingworth ◽  
Angharad Morgan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Genome Wide Association ◽  
Dna Pooling ◽  
Genome Wide ◽  
A Genome

A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population

2015 ◽  
Vol 25 (4) ◽  
pp. 139-146 ◽  
Author(s):  
Atsushi Hirano ◽  
Tomoyuki Ohara ◽  
Atsushi Takahashi ◽  
Masayuki Aoki ◽  
Yuta Fuyuno ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

P3-196: A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

2008 ◽  
Vol 4 ◽  
pp. T578-T578 ◽  
Author(s):  
Richard Abraham ◽  
Lyudmila Georgieva ◽  
Rebecca Sims ◽  
Angharad Morgan ◽  
Paul Hollingworth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Genome Wide Association ◽  
Dna Pooling ◽  
Genome Wide ◽  
A Genome

scholarly journals GWAS identifies 10 loci for objectively-measured physical activity and sleep with causal roles in cardiometabolic disease.

2018 ◽  
Author(s):  
Aiden Doherty ◽  
Karl Smith-Bryne ◽  
Teresa Ferreira ◽  
Michael V Holmes ◽  
Chris Holmes ◽  
...  
Keyword(s):  
Physical Activity ◽  
Blood Pressure ◽  
Genome Wide Association Study ◽  
Moderate Intensity ◽  
Uk Biobank ◽  
Fat Percentage ◽  
Genome Wide ◽  
A Genome ◽  
Pathway Analyses ◽  
Objectively Measured

Physical activity and sleep disorders are established risk factors for many diseases, but their etiology is poorly understood, partly due to a reliance on self-reported evidence. Here we report a genome-wide association study (GWAS) of wearable-defined and machine-learned physical activity and sleep phenotypes in 91,112 UK Biobank participants, and self-reported physical activity in 351,154 UK Biobank participants. While the self-reported activity analysis resulted in no significant (p<5x10-9) loci, the analysis of objectively-measured traits identified 10 loci, 6 of which are novel. These 10 loci account for 0.05% of activity and 0.33% of sleep phenotype variation, but genome-wide estimates suggest that common variation accounts for ~12% of phenotypic variation, indicating high polygenicity. Heritability was higher in women than in men for overall activity (Δh2 = 4%, p=6.3x10-5), moderate intensity activity (6%, p=6.7x10-8), and walking (5%, p=2.6x10-6). Heritability partitioning, enrichment and pathway analyses all indicate the central nervous system plays a role in activity behaviours. Mendelian randomization in publicly available GWAS data and in 278,367 UK Biobank participants, who were not included in our discovery analyses, suggest that overall activity might be causally related to lowering body fat percentage (beta per SD higher overall activity: -0.44, SE=0.047, p=2.70x10-21) and systolic blood pressure (beta per SD: -0.71, SE=0.125, p=1.38x10-8). Our current results advocate the value of physical activity for the reduction of adiposity and blood pressure.

scholarly journals Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

2018 ◽  
Author(s):  
John A. Lees ◽  
Bart Ferwerda ◽  
Philip H. C. Kremer ◽  
Nicole E. Wheeler ◽  
Mercedes Valls Serón ◽  
...  
Keyword(s):  
Pneumococcal Disease ◽  
Pneumococcal Meningitis ◽  
Genome Wide Association Study ◽  
Interaction Analysis ◽  
Invasive Potential ◽  
Genome Wide ◽  
A Genome ◽  
Invasive Diseases ◽  
Life Threatening ◽  
Variation Explained

AbstractStreptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

scholarly journals Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UKBiobank

2016 ◽  
Author(s):  
Jacqueline M Lane ◽  
Irma Vlasac ◽  
Simon G Anderson ◽  
Simon Kyle ◽  
William G Dixon ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Genome Wide Association Study ◽  
Biological Clock ◽  
Genome Wide Association ◽  
Light Sensing ◽  
Sleep Timing ◽  
Genome Wide ◽  
A Genome ◽  
Higher Educational Attainment ◽  
Pathway Analyses

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here, we perform a genome-wide association study of self-reported chronotype within the UKBiobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans, but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.

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