Publications by authors named "Allison E Ashley-Koch"

81 Publications

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Nat Commun 2020 11 24;11(1):5965. Epub 2020 Nov 24.

Brown University, Psychiatry and Human Behavior, Department of Pediatric Research, Providence, RI, USA.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
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http://dx.doi.org/10.1038/s41467-020-19615-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686485PMC
November 2020

PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.

Nat Commun 2020 11 19;11(1):5903. Epub 2020 Nov 19.

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.

The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia.
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http://dx.doi.org/10.1038/s41467-020-19637-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677393PMC
November 2020

Genetic predictors of hippocampal subfield volume in PTSD cases and trauma-exposed controls.

Eur J Psychotraumatol 2020 Jul 29;11(1):1785994. Epub 2020 Jul 29.

VA Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VAMC, Durham, NC, USA.

Behavioural, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in posttraumatic stress disorder (PTSD) pathogenesis. Recent work in a normative, primarily European, sample identified 15 unique genetic loci contributing to structural variability in six hippocampal subfield volumes. We explored the relevance of these loci in two samples (Mental Illness Research Education and Clinical Centre [MIRECC] and Grady; = 290) of trauma-exposed individuals enriched for PTSD and of diverse ancestry. Four of the previous loci demonstrated nominal evidence of replication in the MIRECC dataset, primarily within non-Hispanic whites (NHW). One locus replicated in the Grady cohort, which was composed exclusively of non-Hispanic blacks (NHB). Our data supported genetic interactions with diagnosis of lifetime PTSD and genetic interactions with childhood trauma in the MIRECC sample, but not the Grady sample. Given the racial, diagnostic, and trauma-exposure differences with the original genome-wide association study (GWAS) report, we conducted a full GWAS in the MIRECC and Grady datasets. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for single nucleotide polymorphisms (SNPs) with evidence of main effects. Genetic associations surpassed false discovery rate (FDR)-correction within hippocampal subfields in fimbria, subiculum, cornu ammonis-1 (CA1), and hippocampal amygdala transition area (HATA). One association was replicated in the Grady cohort (rs12880795 in with left (L)-HATA volume). The most significant association in the MIRECC dataset was between rs6906714 in and right (R)-fimbria volume ( = 5.99×10, = 0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with exposure to childhood trauma (gene*environment [G*E] interaction = 0.022). These preliminary results argue for G*E interactions between genetic loci with PTSD and childhood trauma on hippocampal phenotypes. Our results underscore the need for larger neuroimaging-genetic studies in PTSD, trauma, and ancestrally diverse populations.
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http://dx.doi.org/10.1080/20008198.2020.1785994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473168PMC
July 2020

Potential causal role of l-glutamine in sickle cell disease painful crises: A Mendelian randomization analysis.

Blood Cells Mol Dis 2021 Feb 10;86:102504. Epub 2020 Sep 10.

Montreal Heart Institute, Montréal, Québec, Canada; Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address:

In a recent clinical trial, the metabolite l-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To support this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a potential causal relationship between l-glutamine levels and painful crises (N = 1278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52-0.89], P = 0.0048). In two smaller SCD cohorts (N = 299 and 406), the protective effect of l-glutamine was observed (OR = 0.82 [0.50-1.34]), although the MR result was not significant (P = 0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid were associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.
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http://dx.doi.org/10.1016/j.bcmd.2020.102504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686124PMC
February 2021

Serum albumin is independently associated with higher mortality in adult sickle cell patients: Results of three independent cohorts.

PLoS One 2020 10;15(8):e0237543. Epub 2020 Aug 10.

Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Sickle cell disease (SCD) impacts liver and kidney function as well as skin integrity. These complications, as well as the hyperinflammatory state of SCD, could affect serum albumin. Serum albumin has key roles in antioxidant, anti-inflammatory and antithrombotic pathways and maintains vascular integrity. In SCD, these pathways modulate disease severity and clinical outcomes. We used three independent SCD adult cohorts to assess clinical predictors of serum albumin as well its association with mortality. In 2553 SCD adult participants, the frequency of low (<35 g/L) serum albumin was 5%. Older age and lower hemoglobin (P <0.001) were associated with lower serum albumin in all three cohorts. In age and hemoglobin adjusted analysis, higher liver enzymes (P <0.05) were associated with lower serum albumin. In two of the three cohorts, lower kidney function as measured by Glomerular Filtration Rate (P<0.001) was associated with lower serum albumin. Lower serum albumin predicted higher risk of tricuspid regurgitation velocity ≥ 2.5 m/s (OR = 1.1 per g/L, P ≤0.01). In all three cohorts, patients with low serum albumin had higher mortality (adjusted HR ≥2.9, P ≤0.003). This study confirms the role of serum albumin as a biomarker of disease severity and prognosis in patients with SCD. Albumin as a biomarker and possible mediator of SCD severity should be studied further.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237543PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416942PMC
October 2020

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.

Clin Epigenetics 2020 03 14;12(1):46. Epub 2020 Mar 14.

Arq, Psychotrauma Reseach Expert Group, Diemen, NH, Netherlands.

Background: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD).

Methods: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72).

Results: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10, p = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10, p = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10, p = 0.042).

Conclusions: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.
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http://dx.doi.org/10.1186/s13148-020-0820-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071645PMC
March 2020

Genetic variation in dopamine neurotransmission and motor development of infants born extremely-low-birthweight.

Dev Med Child Neurol 2020 06 6;62(6):750-757. Epub 2019 Nov 6.

Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Aim: To determine if genetic variation associated with decreased dopamine neurotransmission predicts a decrease in motor development in a convenience cohort study of infants born extremely-low-birthweight (ELBW).

Method: Four hundred and ninety-eight infants born ELBW had genome-wide genotyping and a neurodevelopmental evaluation at 18 to 22 months of age, corrected for preterm birth. A polygenic risk score (PRS) was created to combine into one predictor variable the hypothesized influences on motor development of alleles at seven independent single nucleotide polymorphisms previously associated with relative decreases in both dopamine neurotransmission and motor learning, by summing the number of alleles present in each infant (range=0-14). The motor development outcome was the Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development, Second Edition. The linear regression models were adjusted for seven clinical and four genetic ancestry covariates. The mean PRS of infants with cerebral palsy (CP) was compared to those without CP.

Results: PRS was inversely related to PDI (p=0.011). Each 1-point increase in PRS resulted in an average decrease in PDI of 1.37 points. Patients with CP did not have a greater mean PRS than those without (p=0.67), both with and without adjustment for covariates.

Interpretation: Genetic variation that favors a decrease in dopamine neurotransmission predisposes to a decrease in motor development in infants born ELBW, but not to the diagnosis of CP.

What This Paper Adds: Genetic variation in dopamine neurotransmission was associated with a decrease in motor development in infants born at an extremely-low-birthweight. It does not predispose to the diagnosis of cerebral palsy.
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http://dx.doi.org/10.1111/dmcn.14383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200269PMC
June 2020

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

JAMA 2019 11;322(17):1682-1691

Clayton Eye Care Center Management Inc, Marrow, Georgia.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.

Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.

Design, Settings, And Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.

Exposures: Genetic variants associated with primary open-angle glaucoma.

Main Outcomes And Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.

Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.

Conclusions And Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
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http://dx.doi.org/10.1001/jama.2019.16161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865235PMC
November 2019

A Genocentric Approach to Discovery of Mendelian Disorders.

Am J Hum Genet 2019 11 24;105(5):974-986. Epub 2019 Oct 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849092PMC
November 2019

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Nat Commun 2019 10 8;10(1):4558. Epub 2019 Oct 8.

Durham VA Medical Center, Research, Durham, NC, USA.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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http://dx.doi.org/10.1038/s41467-019-12576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783435PMC
October 2019

RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes.

PLoS One 2019 3;14(6):e0217042. Epub 2019 Jun 3.

Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States of America.

Kidney failure occurs in 5-13% of individuals with sickle cell disease and is associated with early mortality. Two APOL1 alleles (G1 and G2) have been identified as risk factors for sickle cell disease nephropathy. Both risk alleles are prevalent in individuals with recent African ancestry and have been associated with nephropathic complications in other diseases. Despite the association of G1 and G2 with kidney dysfunction, the mechanisms by which these variants contribute to increased risk remain poorly understood. Previous work in zebrafish models suggest that the G2 risk allele functions as a dominant negative, whereas the G1 allele is a functional null. To understand better the cellular pathology attributed to APOL1 G2, we investigated the in vivo effects of the G2 risk variant on distinct cell types using RNA sequencing. We surveyed APOL1 G2 associated transcriptomic alterations in podocytes and vascular endothelial cells isolated from zebrafish larvae expressing cell-type specific reporters. Our analysis identified many transcripts (n = 7,523) showing differential expression between APOL1 G0 (human wild-type) and APOL1 G2 exposed podocytes. Conversely, relatively few transcripts (n = 107) were differentially expressed when comparing APOL1 G0 and APOL1 G2 exposed endothelial cells. Pathway analysis of differentially expressed transcripts in podocytes showed enrichment for autophagy associated terms such as "Lysosome" and "Phagosome", implicating these pathways in APOL1 G2 associated kidney dysfunction. This work provides insight into the molecular pathology of APOL1 G2 nephropathy which may offer new therapeutic strategies for multiple disease contexts such as sickle cell nephropathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217042PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546218PMC
February 2020

A multi-institutional comparison of younger and older adults with sickle cell disease.

Am J Hematol 2019 04 31;94(4):E115-E117. Epub 2019 Jan 31.

Division of Hematology, Duke University School of Medicine, Durham, North Carolina.

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http://dx.doi.org/10.1002/ajh.25405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449149PMC
April 2019

A multi-institutional comparison of younger and older adults with sickle cell disease.

Am J Hematol 2019 04 31;94(4):E115-E117. Epub 2019 Jan 31.

Division of Hematology, Duke University School of Medicine, Durham, North Carolina.

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http://dx.doi.org/10.1002/ajh.25405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449149PMC
April 2019

Clinical and metabolomic risk factors associated with rapid renal function decline in sickle cell disease.

Am J Hematol 2018 12 27;93(12):1451-1460. Epub 2018 Sep 27.

Department of Medicine, Division of Hematology and Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, North Carolina.

Sickle cell disease (SCD) nephropathy and lower estimated glomerular filtration rate (eGFR) are risk factors for early mortality. Furthermore, rate of eGFR decline predicts progression to end-stage renal disease in many clinical settings. However, factors predicting renal function decline in SCD are poorly documented. Using clinical, laboratory, genetic, and metabolomic data, we evaluated predictors of renal function decline in a longitudinal cohort of 288 adults (mean age 33.0 years). In 193 subjects with 5-year follow-up data, mean rate of eGFR decline was 2.35 mL/min/1.73 m /year, nearly twice that of African American adults overall. Hyperfiltration was prevalent at baseline (61.1%), and 36.8% of subjects experienced rapid eGFR decline (≥3 mL/min/1.73 m /year). Severe Hb genotype; proteinuria; higher platelet and reticulocyte counts, and systolic BP; and lower Hb level and BMI were associated with rapid decline. A risk scoring system was created using these 7 variables and was highly predictive of rapid eGFR decline, with odds of rapid decline increasing 1.635-fold for every point increment (P < 0.0001). Rapid eGFR decline was also associated with higher organ system severity score and peak creatinine. Additionally, two metabolites (asymmetric dimethylarginine and quinolinic acid) were associated with rapid decline. Further investigation into longitudinal SCD nephropathy (SCDN) trajectory, early markers of SCDN, and tools for risk stratification should inform interventional studies targeted to slowing GFR decline and improving SCD outcomes.
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http://dx.doi.org/10.1002/ajh.25263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397774PMC
December 2018

Genomic Approaches to Posttraumatic Stress Disorder: The Psychiatric Genomic Consortium Initiative.

Biol Psychiatry 2018 05 2;83(10):831-839. Epub 2018 Feb 2.

Carl R. Woese Institute for Genomic Biology, University of Illinois-Urbana-Champaign, Champaign, Illinois; Department of Psychology, University of Illinois-Urbana-Champaign, Champaign, Illinois.

Posttraumatic stress disorder (PTSD) after exposure to a traumatic event is a highly prevalent psychiatric disorder. Heritability estimates from twin studies as well as from recent molecular data (single nucleotide polymorphism-based heritability) indicate moderate to high heritability, yet robust genetic variants for PTSD have not yet been identified and the genetic architecture of this polygenic disorder remains largely unknown. To date, fewer than 10 large-scale genome-wide association studies of PTSD have been published, with findings that highlight the unique challenges for PTSD genomics, including a complex diagnostic entity with contingency of PTSD diagnosis on trauma exposure and the large genetic diversity of the study populations. The Psychiatric Genomics Consortium PTSD group has brought together more than 200 scientists with the goal to increase sample size for genome-wide association studies and other genomic analyses to sufficient numbers where robust discoveries of molecular signatures can be achieved. The sample currently includes more than 32,000 PTSD cases and 100,000 trauma-exposed control subjects, and collection is ongoing. The first results found a significant shared genetic risk of PTSD with other psychiatric disorders and sex-biased heritability estimates with higher heritability in female individuals compared with male individuals. This review describes the scope and current focus of the Psychiatric Genomics Consortium PTSD group and its expansion from the initial genome-wide association study group to nine working groups, including epigenetics, gene expression, imaging, and integrative systems biology. We further briefly outline recent findings and future directions of "omics"-based studies of PTSD, with the ultimate goal of elucidating the molecular architecture of this complex disorder to improve prevention and intervention strategies.
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http://dx.doi.org/10.1016/j.biopsych.2018.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915904PMC
May 2018

Traumatic stress and accelerated DNA methylation age: A meta-analysis.

Psychoneuroendocrinology 2018 06 27;92:123-134. Epub 2017 Dec 27.

Department of Psychiatry and Behavioral Sciences, Emory University, United States; Department of Gynecology and Obstetrics, Emory University, United States.

Background: Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results.

Methods: We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables.

Results: Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors.

Conclusions: Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.
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http://dx.doi.org/10.1016/j.psyneuen.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924645PMC
June 2018

Genome-wide association study of subcortical brain volume in PTSD cases and trauma-exposed controls.

Transl Psychiatry 2017 11 30;7(11):1265. Epub 2017 Nov 30.

Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VAMC, Durham, NC, USA.

Depending on the traumatic event, a significant fraction of trauma survivors subsequently develop PTSD. The additional variability in PTSD risk is expected to arise from genetic susceptibility. Unfortunately, several genome-wide association studies (GWAS) have failed to identify a consistent genetic marker for PTSD. The heritability of intermediate phenotypes such as regional brain volumes is often 80% or higher. We conducted a GWAS of subcortical brain volumes in a sample of recent military veteran trauma survivors (n = 157), grouped into PTSD (n = 66) and non-PTSD controls (n = 91). Covariates included PTSD diagnosis, sex, intracranial volume, ancestry, childhood trauma, SNP×PTSD diagnosis, and SNP×childhood trauma. We identified several genetic markers in high linkage disequilibrium (LD) with rs9373240 (p = 2.0 × 10, FDR q = 0.0375) that were associated with caudate volume. We also observed a significant interaction between rs9373240 and childhood trauma (p-values = 0.0007-0.002), whereby increased trauma exposure produced a stronger association between SNPs and increased caudate volume. We identified several SNPs in high LD with rs34043524, which is downstream of the TRAM1L1 gene that were associated with right lateral ventricular volume (p = 1.73 × 10; FDR q = 0.032) and were also associated with lifetime alcohol abuse or dependence (p = 2.49 × 10; FDR q = 0.0375). Finally, we identified several SNPs in high LD with rs13140180 (p = 2.58 × 10; FDR q = .0016), an intergenic region on chromosome 4, and several SNPs in the TMPRSS15 associated with right nucleus accumbens volume (p = 2.58 × 10; FDR q = 0.017). Both TRAM1L1 and TMPRSS15 have been previously implicated in neuronal function. Key results survived genome-wide multiple-testing correction in our sample. Leveraging neuroimaging phenotypes may offer a shortcut, relative to clinical phenotypes, in mapping the genetic architecture and neurobiological pathways of PTSD.
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http://dx.doi.org/10.1038/s41398-017-0021-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802459PMC
November 2017

Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline.

Am J Med Genet B Neuropsychiatr Genet 2017 Sep 10;174(6):619-630. Epub 2017 Jul 10.

Mental Illness Research, Education, and Clinical Center, VA Mid-Atlantic, Durham, North Carolina.

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.
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http://dx.doi.org/10.1002/ajmg.b.32568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592721PMC
September 2017

The association of single-nucleotide polymorphisms in the oxytocin receptor and G protein-coupled receptor kinase 6 (GRK6) genes with oxytocin dosing requirements and labor outcomes.

Am J Obstet Gynecol 2017 09 17;217(3):367.e1-367.e9. Epub 2017 May 17.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University, Durham, NC.

Background: Oxytocin is a potent uterotonic agent that is widely used for induction and augmentation of labor. Oxytocin has a narrow therapeutic index and the optimal dosing for any individual woman varies widely.

Objective: The objective of this study was to determine whether genetic variation in the oxytocin receptor (OXTR) or in the gene encoding G protein-coupled receptor kinase 6 (GRK6), which regulates desensitization of the oxytocin receptor, could explain variation in oxytocin dosing and labor outcomes among women being induced near term.

Study Design: Pregnant women with a singleton gestation residing in Durham County, NC, were prospectively enrolled as part of the Healthy Pregnancy, Healthy Baby cohort study. Those women undergoing an induction of labor at 36 weeks or greater were genotyped for 18 haplotype-tagging single-nucleotide polymorphisms in OXTR and 7 haplotype-tagging single-nucleotide polymorphisms in GRK6 using TaqMan assays. Linear regression was used to examine the relationship between maternal genotype and maximal oxytocin infusion rate, total oxytocin dose received, and duration of labor. Logistic regression was used to test for the association of maternal genotype with mode of delivery. For each outcome, backward selection techniques were utilized to control for important confounding variables and additive genetic models were used. Race/ethnicity was included in all models because of differences in allele frequencies across populations, and Bonferroni correction for multiple testing was used.

Results: DNA was available from 482 women undergoing induction of labor at 36 weeks or greater. Eighteen haplotype-tagging single-nucleotide polymorphisms within OXTR and 7 haplotype-tagging single-nucleotide polymorphisms within GRK6 were examined. Five single-nucleotide polymorphisms in OXTR showed nominal significance with maximal infusion rate of oxytocin, and two single-nucleotide polymorphisms in OXTR were associated with total oxytocin dose received. One single-nucleotide polymorphism in OXTR and two single-nucleotide polymorphisms in GRK6 were associated with duration of labor, one of which met the multiple testing threshold (P = .0014, rs2731664 [GRK6], mean duration of labor, 17.7 hours vs 20.2 hours vs 23.5 hours for AA, AC, and CC genotypes, respectively). Three single-nucleotide polymorphisms, two in OXTR and one in GRK6, showed nominal significance with mode of delivery.

Conclusion: Genetic variation in OXTR and GRK6 is associated with the amount of oxytocin required as well as the duration of labor and risk for cesarean delivery among women undergoing induction of labor near term. With further research, pharmacogenomic approaches may potentially be utilized to develop personalized treatment to improve safety and efficacy outcomes among women undergoing induction of labor.
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http://dx.doi.org/10.1016/j.ajog.2017.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581254PMC
September 2017

Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration.

Invest Ophthalmol Vis Sci 2017 03;58(3):1570-1576

Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, United States 2Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, United States.

Purpose: Genome-wide association (GWAS) and sequencing studies for AMD have highlighted the importance of coding variants at loci that encode components of the complement pathway. However, assessing the contribution of such alleles to AMD, especially when they are rare, remains coarse, in part because of the persistent challenge in establishing their functional relevance. Others and we have shown previously that rare alleles in complement factor I (CFI) can be tested functionally using a surrogate in vivo assay of retinal vascularization in zebrafish embryos. Here, we have implemented and scaled these tools to assess the overall contribution of rare alleles in CFI to AMD.

Methods: We performed targeted sequencing of CFI in 731 AMD patients, followed by replication in a second patient cohort of 511 older healthy individuals. Systematic functional testing of all alleles and post-hoc statistical analysis of functional variants was also performed.

Results: We discovered 20 rare coding nonsynonymous variants, including the previously reported G119R allele. In vivo testing led to the identification of nine variants that alter CFI; six of which are associated with hypoactive complement factor I (FI). Post-hoc analysis in ethnically matched, population controls showed six of these to be present exclusively in cases.

Conclusions: Taken together, our data argue that multiple rare and ultra-rare alleles in CFI contribute to AMD pathogenesis; they improve the precision of the assessment of the contribution of CFI to AMD; and they offer a rational route to establishing both causality and direction of allele effect for genes associated with this disorder.
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http://dx.doi.org/10.1167/iovs.16-20867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022411PMC
March 2017

Further evidence for a role of the ADRB2 gene in risk for posttraumatic stress disorder.

J Psychiatr Res 2017 01 17;84:59-61. Epub 2016 Sep 17.

Department of Medicine, Duke University Medical Center, Durham, NC, United States; Duke Center for Human Disease Modeling, Durham, NC, United States.

The aim of the present study was to attempt to replicate the recently reported finding associating rs2400707 of the Adrenoceptor Beta 2, Surface (ADRB2) gene and childhood trauma on PTSD symptoms. Participants included a predominantly veteran cohort of non-Hispanic blacks (NHB; n = 949) and a pre-dominantly veteran cohort of non-Hispanic whites (NHW; n = 759). No main effects were observed for rs2400707 on PTSD diagnosis. Among the NHB participants, we observed an interaction between rs2400707 and history of childhood trauma, whereby with each additional A allele, the odds of having PTSD increased by 1.31, but only among those who had experienced childhood trauma (p = 0.038). The interaction with rs2400707 and childhood trauma was not observed among the NHW study participants (p = 0.892). Taken together, the findings from the present research provide further evidence that the adrenergic system may be an important modulator of PTSD risk; however, additional work is still needed to clarify the exact nature of the relationship between PTSD and rs2400707 of the ADRB2 gene.
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http://dx.doi.org/10.1016/j.jpsychires.2016.09.013DOI Listing
January 2017

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease.

PLoS One 2016 12;11(4):e0152895. Epub 2016 Apr 12.

Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States of America.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients. Trial registration: ClinicalTrials.gov NCT01715480.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829228PMC
August 2016

Linkage of familial essential tremor to chromosome 5q35.

Mov Disord 2016 07 26;31(7):1059-62. Epub 2016 Feb 26.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.

Background: Essential tremor is a neurological condition characterized by tremor during voluntary movement. To date, 3 loci linked to familial essential tremor have been identified.

Methods: We examined 48 essential tremor patients in 5 large essential tremor pedigrees in our data set for genetic linkage using an Affymetrix Axiom array. Linkage analysis was performed using an affecteds-only dominant model in SIMWALK2. To incorporate all genotype information, GERMLINE was used to identify genome segments shared identical-by-descent in pairs of affecteds. Exome sequencing was performed in pedigrees showing evidence of linkage.

Results: For one family, chromosomes 5 and 18 showed genome-wide significant linkage to essential tremor. Shared segment analysis excluded the 18p11 candidate region and reduced the 5q35 region by 1 megabase. Exome sequencing did not identify a potential causative variant in this region.

Conclusion: A locus on chromosome 5 is linked to essential tremor. Further research is needed to identify a causative variant. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26582DOI Listing
July 2016

Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.

Hum Mol Genet 2015 Nov 25;24(22):6552-63. Epub 2015 Aug 25.

Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa and.

Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (∼40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-defined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1. We show that this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddv347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614704PMC
November 2015

Evidence for fumonisin inhibition of ceramide synthase in humans consuming maize-based foods and living in high exposure communities in Guatemala.

Mol Nutr Food Res 2015 Nov 3;59(11):2209-24. Epub 2015 Sep 3.

Department of Pharmacology, School of Medicine, Creighton University, Omaha, NE, USA.

Scope: Fumonisin (FB) occurs in maize and is an inhibitor of ceramide synthase (CerS). We determined the urinary FB1 (UFB1 ) and sphingoid base 1-phosphate levels in blood from women consuming maize in high and low FB exposure communities in Guatemala.

Methods And Results: FB1 intake was estimated using the UFB1 . Sphinganine 1-phosphate (Sa 1-P), sphingosine 1-phosphate (So 1-P), and the Sa 1-P/So 1-P ratio were determined in blood spots collected on absorbent paper at the same time as urine collection. In the first study, blood spots and urine were collected every 3 months (March 2011 to February 2012) from women living in low (Chimaltenango and Escuintla) and high (Jutiapa) FB exposure communities (1240 total recruits). The UFB1 , Sa 1-P/So 1-P ratio, and Sa 1-P/mL in blood spots were significantly higher in the high FB1 intake community compared to the low FB1 intake communities. The results were confirmed in a follow-up study (February 2013) involving 299 women living in low (Sacatepéquez) and high (Santa Rosa and Chiquimula) FB exposure communities.

Conclusions: High levels of FB1 intake are correlated with changes in Sa 1-P and the Sa 1-P/So 1-P ratio in human blood in a manner consistent with FB1 inhibition of CerS.
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http://dx.doi.org/10.1002/mnfr.201500499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956729PMC
November 2015