Publications by authors named "David W Clark"

49 Publications

Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Hepatol Commun 2021 Sep 17. Epub 2021 Sep 17.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edingburgh, Scotland.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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http://dx.doi.org/10.1002/hep4.1805DOI Listing
September 2021

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

J Hum Genet 2021 Jun 20;66(6):625-636. Epub 2021 Jan 20.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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http://dx.doi.org/10.1038/s10038-020-00895-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144017PMC
June 2021

Autozygosity influences cardiometabolic disease-associated traits in the AWI-Gen sub-Saharan African study.

Nat Commun 2020 11 13;11(1):5754. Epub 2020 Nov 13.

Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

The analysis of the effects of autozygosity, measured as the change of the mean value of a trait among offspring of genetic relatives, reveals the existence of directional dominance or overdominance. In this study we detect evidence of the effect of autozygosity in 4 out of 13 cardiometabolic disease-associated traits using data from more than 10,000 sub-Saharan African individuals recruited from Ghana, Burkina Faso, Kenya and South Africa. The effect of autozygosity on these phenotypes is found to be sex-related, with inbreeding having a significant decreasing effect in men but a significant increasing effect in women for several traits (body mass index, subcutaneous adipose tissue, low-density lipoproteins and total cholesterol levels). Overall, the effect of inbreeding depression is more intense in men. Differential effects of inbreeding depression are also observed between study sites with different night-light intensity used as proxy for urban development. These results suggest a directional dominant genetic component mediated by environmental interactions and sex-specific differences in genetic architecture for these traits in the Africa Wits-INDEPTH partnership for Genomic Studies (AWI-Gen) cohort.
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http://dx.doi.org/10.1038/s41467-020-19595-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666169PMC
November 2020

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

PLoS Genet 2020 07 6;16(7):e1008785. Epub 2020 Jul 6.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, United Kingdom.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.
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http://dx.doi.org/10.1371/journal.pgen.1008785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337286PMC
July 2020

The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability.

Oncogene 2020 03 27;39(12):2583-2596. Epub 2020 Jan 27.

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Centre, Lubbock, TX, 79430, USA.

Phosphofurin acidic cluster sorting protein-1 (PACS-1) is a multifunctional membrane traffic regulator that plays important roles in organ homeostasis and disease. In this study, we elucidate a novel nuclear function for PACS-1 in maintaining chromosomal integrity. PACS-1 progressively accumulates in the nucleus during cell cycle progression, where it interacts with class I histone deacetylases 2 and 3 (HDAC2 and HDAC3) to regulate chromatin dynamics by maintaining the acetylation status of histones. PACS-1 knockdown results in the proteasome-mediated degradation of HDAC2 and HDAC3, compromised chromatin maturation, as indicated by elevated levels of histones H3K9 and H4K16 acetylation, and, consequently, increased replication stress-induced DNA damage and genomic instability.
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http://dx.doi.org/10.1038/s41388-020-1167-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085454PMC
March 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

The genetic landscape of Scotland and the Isles.

Proc Natl Acad Sci U S A 2019 09 3;116(38):19064-19070. Epub 2019 Sep 3.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland;

Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data for 2,554 individuals from across the entire archipelago with geographically restricted ancestry, and performed population structure analyses and comparisons to ancient DNA. Extensive geographic structuring is revealed, from broad scales such as a NE to SW divide in mainland Scotland, through to the finest scale observed to date: across 3 km in the Northern Isles. Many genetic boundaries are consistent with Dark Age kingdoms of Gaels, Picts, Britons, and Norse. Populations in the Hebrides, the Highlands, Argyll, Donegal, and the Isle of Man show characteristics of isolation. We document a pole of Norwegian ancestry in the north of the archipelago (reaching 23 to 28% in Shetland) which complements previously described poles of Germanic ancestry in the east, and "Celtic" to the west. This modern genetic structure suggests a northwestern British or Irish source population for the ancient Gaels that contributed to the founding of Iceland. As rarer variants, often with larger effect sizes, become the focus of complex trait genetics, more diverse rural cohorts may be required to optimize discoveries in British and Irish populations and their considerable global diaspora.
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http://dx.doi.org/10.1073/pnas.1904761116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754546PMC
September 2019

Publisher Correction: Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.

Nat Commun 2019 May 1;10(1):2069. Epub 2019 May 1.

MRC Human Genetic Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

In the original version of this Article, the legend in the upper panel of Figure 2 incorrectly read 'paternal imprinting' and should have read 'maternal imprinting'. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-10155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494888PMC
May 2019

Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.

Nat Commun 2019 03 27;10(1):1383. Epub 2019 Mar 27.

MRC Human Genetic Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.
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http://dx.doi.org/10.1038/s41467-019-09301-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437195PMC
March 2019

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Nat Genet 2019 02 14;51(2):245-257. Epub 2019 Jan 14.

Team Loyalty BV, Hoofddorp, the Netherlands.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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http://dx.doi.org/10.1038/s41588-018-0309-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713272PMC
February 2019

Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.

Elife 2019 01 15;8. Epub 2019 Jan 15.

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom.

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.3/ and , whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.39856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333444PMC
January 2019

International assessment of inter- and intrarater reliability of the International Frontal Sinus Anatomy Classification system.

Int Forum Allergy Rhinol 2019 01 14;9(1):39-45. Epub 2018 Sep 14.

Department of Otolaryngology-Head and Neck Surgery, University of Texas Health San Antonio, San Antonio, TX.

Background: Inconsistencies in the nomenclature of structures of the frontal sinus have impeded the development of a validated "reference standard" classification system that surgeons can reliably agree upon. The International Frontal Sinus Anatomy Classification (IFAC) system was developed as a consensus document, based on expert opinion, attempting to address this issue. The purposes of this study are to: establish the reliability of the IFAC as a tool for classifying cells in the frontal recess among an international group of rhinologists; and improve communication and teaching of frontal endoscopic sinus surgery (ESS).

Methods: Forty-two computed tomography (CT) scans, each with a marked frontal cell, were reviewed by 15 international fellowship-trained rhinologists. Each marked cell was classified into 1 of 7 categories described in the IFAC, on 2 occasions separated by 2 weeks. Inter- and intrarater reliability were evaluated using Light's kappa (κ), the interclass correlation coefficient (ICC), and simple proportion of agreement.

Results: Interrater reliability showed pairwise κ values ranging from 0.7248 to 1.0, with a mean of 0.9162 (SD, 0.0537). The ICC was 0.98. Intrarater reliability showed κ values ranging from 0.8613 to 1.0, with a mean of 0.9407 (SD, 0.0376). The within-rater ICC was 0.98.

Conclusion: Among a diverse sample of rhinologists (raters), there was substantial to almost perfect agreement between raters, and among individual raters at different timepoints. The IFAC is a reliable tool for classification of cells in the frontal sinus. Further outcome studies are still needed to determine the validity of the IFAC.
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http://dx.doi.org/10.1002/alr.22200DOI Listing
January 2019

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Nat Genet 2018 07 23;50(8):1112-1121. Epub 2018 Jul 23.

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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http://dx.doi.org/10.1038/s41588-018-0147-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393768PMC
July 2018

Nasal airway obstruction: Prevalence and anatomic contributors.

Ear Nose Throat J 2018 Jun;97(6):173-176

Department of Otolaryngology-Head and Neck Surgery, Baylor Scott & White Health, and Texas A&M Health Science Center College of Medicine, Temple, TX, USA.

Surgical treatments for nasal airway obstruction (NAO) are commonly offered as part of otolaryngology practice. Anatomic causes include septal deviation, inferior turbinate hypertrophy, and nasal valve collapse (NVC). This study was performed to determine the prevalence of anatomic contributors to NAO. A total of 1,906 patients with sinonasal complaints were surveyed by 50 otolaryngologists in varying U.S. geographic regions. Patients were first evaluated using the Nasal Obstruction Symptom Evaluation (NOSE) instrument to assess the NAO symptoms and their severity. Physicians then examined patients for the presence of the three anatomic contributors. Presence of septal deviation and turbinate hypertrophy was assessed through an internal nasal exam with direct or endoscopic visualization based on the physician's standard methodology for diagnosis. Presence of NVC was determined by the modified Cottle maneuver. Among all patients surveyed, prevalence was 67% for NVC, 76% for septal deviation, and 72% for inferior turbinate hypertrophy. We found that 64% of the patients (n = 1,211) had severe/extreme NOSE scores (≥55), representing the most likely nasal obstruction candidates for intervention. In these patients, the prevalence of NVC, septal deviation, and inferior turbinate hypertrophy was 73, 80, and 77%, respectively. Eighty-two percent of the 236 patients with severe/extreme NOSE scores who reported prior septoplasty and/or inferior turbinate reduction had NVC. Our study revealed a comparable prevalence of all three anatomic contributors across all patients and the subset with severe/extreme NOSE scores, highlighting the importance of evaluating the lateral nasal wall as a component of NAO treatment strategy.
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http://dx.doi.org/10.1177/014556131809700615DOI Listing
June 2018

RAD6 promotes chemoresistance in ovarian cancer.

Mol Cell Oncol 2018 18;5(1):e1392403. Epub 2017 Dec 18.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama, USA.

Mortality in ovarian cancer is predominantly due to acquired chemoresistance and tumor recurrence. UBIQUITIN CONJUGATING ENZYME E2 or RAD6 expression increases in cell lines and patient tumors in response to platinum-based chemotherapy and promotes both activation of DNA damage response pathways and expression of stemness genes and a stem cell-like phenotype driving ovarian cancer chemoresistance.
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http://dx.doi.org/10.1080/23723556.2017.1392403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791863PMC
December 2017

Runs of homozygosity: windows into population history and trait architecture.

Nat Rev Genet 2018 04 15;19(4):220-234. Epub 2018 Jan 15.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.
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http://dx.doi.org/10.1038/nrg.2017.109DOI Listing
April 2018

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Nat Commun 2017 10 13;8(1):910. Epub 2017 Oct 13.

Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester, M13 9PL, UK.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
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http://dx.doi.org/10.1038/s41467-017-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715013PMC
October 2017

Submandibular neck mass in a newborn.

Proc (Bayl Univ Med Cent) 2017 Oct;30(4):461-462

Texas A&M Health Science Center College of Medicine (Skoog) and the Department of Otolaryngology-Head & Neck Surgery, Baylor Scott & White Health, Temple, Texas.

A deep neck abscess is uncommon in the newborn period. In this case, we noted a clindamycin-sensitive methicillin-resistant infection characterized as a deep neck abscess in an 8-day-old boy. He was admitted to the pediatric intensive care unit with a progressively enlarging indurated mass below the mandible. Imaging confirmed the mass as a submandibular abscess. The patient received antibiotics in addition to incision and drainage, with resolution of the abscess.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595397PMC
http://dx.doi.org/10.1080/08998280.2017.11930230DOI Listing
October 2017

Multifocal sinonasal inverted papilloma with middle ear involvement.

Proc (Bayl Univ Med Cent) 2017 Oct;30(4):457-458

Division of Otolaryngology, Department of Surgery (Haywood, Hill, Clark) and the Department of Pathology (Olobatuyi), Baylor Scott and White Health and Texas A&M Health Science Center, Temple, Texas; and the Department of Otolaryngology, Augusta University, Augusta, Georgia (Fuller).

Inverted papilloma of the nasal cavity is a benign neoplasm, although it can be locally invasive and has the potential for malignant degeneration. Inverted papilloma of the temporal bone is extremely rare. We describe a case of a 44-year-old woman who was treated for nasal inverted papilloma and was later found to have inverted papilloma of her temporal bone. The patient required several procedures to remove the inverted papilloma from the nasal cavity and temporal bone, and she is currently free of recurrence.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595395PMC
http://dx.doi.org/10.1080/08998280.2017.11930228DOI Listing
October 2017

Bilateral respiratory epithelial adenomatoid hamartomas originating from the anterior olfactory clefts.

Proc (Bayl Univ Med Cent) 2017 Apr;30(2):221-223

Department of Otolaryngology-Head & Neck Surgery, Baylor Scott & White Health, Temple, Texas (Clark) and Texas A&M Health Science Center College of Medicine (Falco, Peine, Clark).

A respiratory epithelial adenomatoid hamartoma (REAH) is an uncommon benign lesion often found in the sinonasal tract. We present a case of bilateral REAH originating from the anterior olfactory cleft treated with endoscopic surgical resection without recurrence. We highlight the characteristics of REAH and necessary steps to ensure proper diagnosis and treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349836PMC
http://dx.doi.org/10.1080/08998280.2017.11929594DOI Listing
April 2017

Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets.

Ann Transl Med 2016 Dec;4(24):518

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.

Resistance to current chemotherapeutic or radiation-based cancer treatment strategies is a serious concern. Cancer stem cells (CSCs) are typically able to evade treatment and establish a recurrent tumor or metastasis, and it is these that lead to the majority of cancer deaths. Therefore, a major current goal is to develop treatment strategies that eliminate the resistant CSCs as well as the bulk tumor cells in order to achieve complete disease clearance. Aldehyde dehydrogenases (ALDHs) are important for maintenance and differentiation of stem cells as well as normal development. There is expanding evidence that ALDH expression increases in response to therapy and promotes chemoresistance and survival mechanisms in CSCs. This perspective will discuss a paper by Cojoc and colleagues recently published in Cancer Research, that indicates ALDHs play a key role in resistance to radiation therapy and tumor recurrence in prostate cancer. The authors suggest that ALDHs are a potential therapeutic target for treatment prostate cancer patients to limit radiation resistance and disease recurrence. The findings are consistent with work from other cancers showing ALDHs are major contributors of CSC signaling and resistance to anti-cancer treatments. This perspective will address representative work concerning the validity of ALDH and the associated retinoic acid signaling pathway as chemotherapeutic targets for prostate as well as other cancers.
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http://dx.doi.org/10.21037/atm.2016.11.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233526PMC
December 2016

Detection and evaluation of estrogen DNA-adducts and their carcinogenic effects in cultured human cells using biotinylated estradiol.

Mol Carcinog 2017 03 21;56(3):1010-1020. Epub 2016 Sep 21.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.

The normal female reproductive hormone estrogen has been linked with increased risk of breast and many other forms of cancer. This is largely due to metabolic conversion of estrogens into highly reactive catechol estrogen quinones which can interact with DNA and cause a variety of DNA adducts and lesions. Detection and analysis of these adducts and their associated cellular responses involve complex chemical, enzymatic, and LC-MS based methods, which are both laborious and require specialized expertise and instrumentation. Herein, we show that using a biotin-labeled estradiol allows immunodetection of estrogen-induced DNA adducts by slot blot and single-cell molecular combing and proximity ligation assays. The biotinylated and unlabeled estradiols induced similar levels of DNA single and double strand breaks as measured by comet assays. Using biotinylated estrogen, we further show that estrogens are able to activate the Fanconi anemia-BRCA tumor suppressor pathway and cause DNA strand breaks and oxidatively modified DNA bases as well as gross chromosomal aberrations. Utilization of biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and associated DNA damage, and to track estrogen adduct-induced cellular responses and carcinogenic mechanisms in cultured cells. The techniques presented here allow simple and rapid detection and quantitation of estrogen adducts by slot blot as well as direct visualization on the DNA strand and could pave the way for developing new treatments to protect the genome from the effects of reactive estrogen metabolites. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mc.22566DOI Listing
March 2017

Rad18 is required for functional interactions between FANCD2, BRCA2, and Rad51 to repair DNA topoisomerase 1-poisons induced lesions and promote fork recovery.

Oncotarget 2016 Mar;7(11):12537-53

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, 36604, USA.

Camptothecin (CPT) and its analogues are chemotherapeutic agents that covalently and reversibly link DNA Topoisomerase I to its nicked DNA intermediate eliciting the formation of DNA double strand breaks (DSB) during replication. The repair of these DSB involves multiple DNA damage response and repair proteins. Here we demonstrate that CPT-induced DNA damage promotes functional interactions between BRCA2, FANCD2, Rad18, and Rad51 to repair the replication-associated DSB through homologous recombination (HR). Loss of any of these proteins leads to equal disruption of HR repair, causes chromosomal aberrations and sensitizes cells to CPT. Rad18 appears to function upstream in this repair pathway as its downregulation prevents activation of FANCD2, diminishes BRCA2 and Rad51 protein levels, formation of nuclear foci of all three proteins and recovery of stalled or collapsed replication forks in response to CPT. Taken together this work further elucidates the complex interplay of DNA repair proteins in the repair of replication-associated DSB.
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http://dx.doi.org/10.18632/oncotarget.7247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914303PMC
March 2016

Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer.

Biochem Biophys Res Commun 2016 Jan 8;469(3):449-55. Epub 2015 Dec 8.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604, USA. Electronic address:

Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression. Furthermore, in ovarian cancer cells Rad6 was found to stabilize β-catenin promoting stem cell-related characteristics, including expression of stem cell markers and anchorage-independent growth. Cancer stem cells can promote chemoresistance, tumor recurrence and metastasis, all of which are limiting factors in treating ovarian cancer. Thus it is significant that Rad6 overexpression led to increased resistance to the chemotherapeutic drug carboplatin and correlated with tumor cell invasion. These findings show the importance of Rad6 in ovarian cancer and emphasize the need for further studies of Rad6 as a potential target for the treatment of ovarian cancer.
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http://dx.doi.org/10.1016/j.bbrc.2015.11.134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715924PMC
January 2016

An oxidative DNA "damage" and repair mechanism localized in the VEGF promoter is important for hypoxia-induced VEGF mRNA expression.

Am J Physiol Lung Cell Mol Physiol 2015 Dec 2;309(11):L1367-75. Epub 2015 Oct 2.

Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, Alabama; and

In hypoxia, mitochondria-generated reactive oxygen species not only stimulate accumulation of the transcriptional regulator of hypoxic gene expression, hypoxia inducible factor-1 (Hif-1), but also cause oxidative base modifications in hypoxic response elements (HREs) of hypoxia-inducible genes. When the hypoxia-induced base modifications are suppressed, Hif-1 fails to associate with the HRE of the VEGF promoter, and VEGF mRNA accumulation is blunted. The mechanism linking base modifications to transcription is unknown. Here we determined whether recruitment of base excision DNA repair (BER) enzymes in response to hypoxia-induced promoter modifications was required for transcription complex assembly and VEGF mRNA expression. Using chromatin immunoprecipitation analyses in pulmonary artery endothelial cells, we found that hypoxia-mediated formation of the base oxidation product 8-oxoguanine (8-oxoG) in VEGF HREs was temporally associated with binding of Hif-1α and the BER enzymes 8-oxoguanine glycosylase 1 (Ogg1) and redox effector factor-1 (Ref-1)/apurinic/apyrimidinic endonuclease 1 (Ape1) and introduction of DNA strand breaks. Hif-1α colocalized with HRE sequences harboring Ref-1/Ape1, but not Ogg1. Inhibition of BER by small interfering RNA-mediated reduction in Ogg1 augmented hypoxia-induced 8-oxoG accumulation and attenuated Hif-1α and Ref-1/Ape1 binding to VEGF HRE sequences and blunted VEGF mRNA expression. Chromatin immunoprecipitation-sequence analysis of 8-oxoG distribution in hypoxic pulmonary artery endothelial cells showed that most of the oxidized base was localized to promoters with virtually no overlap between normoxic and hypoxic data sets. Transcription of genes whose promoters lost 8-oxoG during hypoxia was reduced, while those gaining 8-oxoG was elevated. Collectively, these findings suggest that the BER pathway links hypoxia-induced introduction of oxidative DNA modifications in promoters of hypoxia-inducible genes to transcriptional activation.
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http://dx.doi.org/10.1152/ajplung.00236.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669343PMC
December 2015

FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation.

Oncotarget 2015 Oct;6(30):28816-32

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.

Fanconi anemia (FA) is a rare genome instability syndrome with progressive bone marrow failure and cancer susceptibility. FANCJ is one of 17 genes mutated in FA-patients, comprises a DNA helicase that is vital for properly maintaining genomic stability and is known to function in the FA-BRCA DNA repair pathway. While exact role(s) of FANCJ in this repair process is yet to be determined, it is known to interact with primary effector FANCD2. However, FANCJ is not required for FANCD2 activation but is important for its ability to fully respond to DNA damage. In this report, we determined that transient depletion of FANCJ adversely affects stability of FANCD2 and its co-regulator FANCI in multiple cell lines. Loss of FANCJ does not significantly alter cell cycle progression or FANCD2 transcription. However, in the absence of FANCJ, the majority of FANCD2 is degraded by both the proteasome and Caspase-3 dependent mechanism. FANCJ is capable of complexing with and stabilizing FANCD2 even in the absence of a functional helicase domain. Furthermore, our data demonstrate that FANCJ is important for FANCD2 stability and proper activation of DNA damage responses to replication blocks induced by hydroxyurea.
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http://dx.doi.org/10.18632/oncotarget.5006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745694PMC
October 2015

Staphylococcus aureus prevalence in allergic fungal rhinosinusitis vs other subsets of chronic rhinosinusitis with nasal polyps.

Int Forum Allergy Rhinol 2013 Feb 4;3(2):89-93. Epub 2012 Oct 4.

Division of Otolaryngology-Head and Neck Surgery, Scott and White Hospitals and Clinics, Temple, TX 77030, USA.

Background: The pathogenesis of allergic fungal rhinosinusitis (AFRS) is thought to represent an immunological reaction to fungal antigens. Recent studies have implicated superantigens and non-immunoglobulin E (IgE)-mediated mechanisms in the development of AFRS. The objective of this study is to assess the prevalence of Staphylococcus aureus in AFRS vs other subsets of chronic rhinosinusitis with polyps (CRSwNP, also termed non-AFRS).

Methods: A case series with retrospective review of 19 patients with AFRS and 21 patients with CRSwNP was performed at a tertiary referral center. The diagnosis of AFRS required the presence of defined criteria described by Bent and Kuhn. Bacterial cultures and fungal cultures were analyzed for each group.

Results: S. aureus was significantly more prevalent in the AFRS group compared with the non-AFRS group (63.2% vs 24.1%, p = 0.005).

Conclusion: S. aureus has been implicated as a disease modifier in CRSwNP through superantigen-mediated mechanisms. This study demonstrates a higher prevalence of S. aureus in patients with AFRS vs patients with other subsets of CRSwNP (non-AFRS). These results support a potential role for S. aureus in the pathogenesis of AFRS.
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http://dx.doi.org/10.1002/alr.21090DOI Listing
February 2013

Promoter G-quadruplex sequences are targets for base oxidation and strand cleavage during hypoxia-induced transcription.

Free Radic Biol Med 2012 Jul 1;53(1):51-9. Epub 2012 May 1.

Department of Pharmacology and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.

The G-quadruplex, a non-B DNA motif that forms in certain G-rich sequences, is often located near transcription start sites in growth regulatory genes. Multiple lines of evidence show that reactive oxygen species generated as second messengers during physiologic signaling target specific DNA sequences for oxidative base modifications. Because guanine repeats are uniquely sensitive to oxidative damage, and G4 sequences are known "hot spots" for genetic mutation and DNA translocation, we hypothesized that G4 sequences are targeted for oxidative base modifications in hypoxic signaling. Approximately 25% of hypoxia-regulated genes in pulmonary artery endothelial cells harbored G4 sequences within their promoters. Chromatin immunoprecipitation showed that common base oxidation product 8-oxoguanine was selectively introduced into G4s, in promoters of hypoxia up-, down-, and nonregulated genes. Additionally, base excision DNA repair (BER) enzymes were recruited, and transient strand breaks formed in these sequences. Transcription factor Sp1, constitutively bound to G4 sequences in normoxia, was evicted as 8-oxoguanine accumulated during hypoxic exposure. Blocking hypoxia-induced oxidant production prevented both base modifications and decreased Sp1 binding. These findings suggest that oxidant stress in hypoxia causes oxidative base modifications, recruitment of BER enzymes, and transient strand breaks in G4 promoter sequences potentially altering G4 integrity and function.
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http://dx.doi.org/10.1016/j.freeradbiomed.2012.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377816PMC
July 2012

Chronic rhinosinusitis with nasal polyps: elevated serum immunoglobulin E is associated with Staphylococcus aureus on culture.

Int Forum Allergy Rhinol 2011 Nov-Dec;1(6):445-50. Epub 2011 Jul 18.

University of Texas Medical School at Houston, Department of Otorhinolaryngology-Head and Neck Surgery and Texas Sinus Institute, Houston, TX 77030, USA.

Background: Recent data has implicated Staphylococcus aureus (SA) superantigen as a potential disease modifier in patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). The objective of this work was to compare total serum immunoglobulin E (IgE) and serum eosinophils in patients with CRSwNP and CRS without nasal polyps (CRSsNP) based on culture results of the 3 most commonly isolated bacteria.

Methods: Retrospective review at a tertiary rhinology referral center of patients with CRS over a 4-year period.

Results: Bacterial cultures and immunologic data were obtained from 62 patients with CRSwNP and 34 patients with CRSsNP. SA was the most prevalent bacteria in the CRSwNP group, isolated in 19 patients (31%). Patients with elevated total serum IgE (>114 IU/mL) were more likely to have SA on culture (p = 0.04) in this population. The percent serum eosinophil levels in the SA+ group compared with the SA- group was not significant (6.0 vs 5.1, p = 0.17). Lund-Mackay computed tomography (CT) scores, but not Sino-Nasal Outcome Test 20 (SNOT-20) scores were significantly higher in the SA+ vs SA- group (p = 0.03) in patients with CRSwNP. The CRSsNP group demonstrated no difference in IgE or serum eosinophils between different bacterial groups.

Conclusion: Our findings suggest that there is an association between SA sinonasal presence and elevated total serum IgE in patients with CRSwNP. In addition, SA+ patients had higher Lund-Mackay CT scores, indicating a higher objective burden of disease in this group of patients.
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http://dx.doi.org/10.1002/alr.20079DOI Listing
May 2012

Clinical implications of pharmacogenetic variation on the effects of statins.

Drug Saf 2011 Jan;34(1):1-19

Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.

The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80  million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.
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http://dx.doi.org/10.2165/11584380-000000000-00000DOI Listing
January 2011
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