Publications by authors named "Kathleen Ryan"

205 Publications

Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 15;8(6). Epub 2021 Oct 15.

From the Department of Neurology (C.E.F.), University of Virginia School of Medicine, Charlottesville; Department of Medicine, Microbiology/Immunology and Psychiatry (K.A.R., R.J.N., H.A.W., J.Y.C., J.R.K., B.O., D.W.M., L.H.K.), Dartmouth Medical School, Lebanon, NH; and Department of Neurology (Y.M.-D.), Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor.

Background And Objectives: Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS).

Methods: This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations.

Results: Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment.

Discussion: Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS.

Classification Of Evidence: This study provides Class IV evidence on the safety, pharmacokinetics, and immune effects of an mAb to CD40L in patients with RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000001096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527364PMC
November 2021

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Am J Hum Genet 2021 Oct 27;108(10):1836-1851. Epub 2021 Sep 27.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.007DOI Listing
October 2021

Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.

Hum Mol Genet 2021 Sep 6. Epub 2021 Sep 6.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
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http://dx.doi.org/10.1093/hmg/ddab252DOI Listing
September 2021

Health service utilization and experiences of stigma amongst people who inject drugs in Melbourne, Australia.

J Viral Hepat 2021 Sep 12. Epub 2021 Sep 12.

Disease Elimination Program, Burnet Institute, Melbourne, Vic., Australia.

Whilst the testing and treatment of people who inject drugs (PWID) in Australia is a priority for local hepatitis C (HCV) elimination efforts, perceived stigma related to injecting drug use (IDU) has been identified as a major barrier for PWID engaging in health services. We used data from the EC Experience cohort study to explore associations between IDU-related perceived stigma and the number of different health services accessed by PWID in Melbourne, Australia. Data from the baseline questionnaire were used. Primary outcome was self-reported experience of stigma due to IDU (never, rarely, sometimes, often, always) in the previous 12 months. An ordinal logistic regression model assessed the association between stigma experienced and the number of different health services used (1-2, 3-4, 5-6, 7-10 different services) adjusted for recent IDU and key socio-demographics. Between September 2018 and February 2020, 281 participants were recruited from four health services. Sixty-nine per cent were male, median age was 42, 83% reported past-month IDU, 34% had never tested/tested >12 months, 8% tested negative <12 months, 43% were HCV-positive but not treated and 16% had been treated. Those accessing 5-6 services had 2.2 times greater odds of experiencing stigma (95% CI 0.86-6.65) compared with those using <5 services and those reporting 7-10 services had 2.43 times greater odds of experiencing stigma (95% CI 0.85-6.92) compared with those accessing <7 services. In conclusion, experiences of stigma may not necessarily be a barrier for PWID to access health services, but high rates of health service use may further expose, exacerbate or exaggerate stigma amongst PWID. Further examination of how stigma may be in/directly impact on hepatitis C treatment uptake is important and place-based interventions aimed at reducing stigma experienced by PWID may be needed.
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http://dx.doi.org/10.1111/jvh.13612DOI Listing
September 2021

Neurosurgical intervention in children with ventricular assist devices: A single-center case series review.

Paediatr Anaesth 2021 Nov 17;31(11):1208-1215. Epub 2021 Sep 17.

Division of Pediatric Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: The incidence of neurological complications related to ventricular assist devices (VAD) remains high and includes life-threatening conditions such as intracranial hemorrhage or ischemic stroke. Although no definitive management guidelines exist, operative interventions may be required for major neurological injuries.

Aims: This case series describes the perioperative management of children at a single center who underwent neurosurgical procedures for major intracranial bleeds or ischemic strokes while on VAD support.

Methods: A database review identified all pediatric VAD patients who underwent a neurosurgical procedure for an intracranial hemorrhage or ischemic stroke from April 2014 to January 2020. Data regarding patient characteristics, preoperative medical management, intraoperative anesthetic management, and postoperative outcomes were collected using retrospective chart review.

Results: Ninety VADs were implanted in 78 patients. Five neurosurgical interventions were performed: four for intracranial hemorrhages and one for an ischemic stroke. All four patients with hemorrhages were receiving anticoagulation at the time of their event and the three patients on warfarin received emergent reversal with prothrombin concentrate complex and vitamin K. Three patients also received pre-procedural platelet transfusions. Two of the five procedures were emergent bedside external ventricular drain placements, and three were surgical operations. All three patients who underwent operative procedures received invasive hemodynamic monitoring and were supported with a combination of inotropes and afterload reduction. One patient required a massive blood product transfusion. The two patients who underwent external ventricular drain placement had no further surgical interventions and died from the severity of their neurological injuries. All three patients who underwent operative procedures survived to transplantation and discharge home.

Conclusions: Perioperative concerns for the anesthesiologist include VAD hemodynamic management, bleeding, VAD thrombosis, and prevention of secondary brain injury. A systematic, multidisciplinary approach to management is paramount to attain favorable outcomes.
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http://dx.doi.org/10.1111/pan.14287DOI Listing
November 2021

An Unusual Visit from an Old Foe: Oral Presentation of Syphilis in a Teenage Patient.

Case Rep Pediatr 2021 16;2021:7755914. Epub 2021 Aug 16.

Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.

The authors report an atypical case of secondary syphilis in an adolescent female presenting to a tertiary-care center with fever, weight loss, oral sores, painful inguinal lymphadenopathy, and transient macular rash. Given the lower prevalence of syphilis in adolescent females, this infection was not included on the initial differential diagnosis. The evolving presentation of syphilis over time complicates the diagnosis and management of these infections, as it did for the patient in this report. The authors provide a detailed discussion of the patient's clinical findings, including the protean features of syphilis infection. This case is particularly relevant to the fields of general pediatrics and pediatric hospital medicine.
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http://dx.doi.org/10.1155/2021/7755914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382559PMC
August 2021

Evaluation of Seizure Risk in Infants After Cardiopulmonary Bypass in the Absence of Deep Hypothermic Cardiac Arrest.

Neurocrit Care 2021 Jul 28. Epub 2021 Jul 28.

Division of Child Neurology, Lucile Packard Children's Hospital at Stanford University, Dr Levy 750 Welch Road Suite 317, Palo Alto, CA, USA.

Background: Guidelines recommend evaluation for electrographic seizures in neonates and children at risk, including after cardiopulmonary bypass (CPB). Although initial research using screening electroencephalograms (EEGs) in infants after CPB found a 21% seizure incidence, more recent work reports seizure incidences ranging 3-12%. Deep hypothermic cardiac arrest was associated with increased seizure risk in prior reports but is uncommon at our institution and less widely used in contemporary practice. This study seeks to establish the incidence of seizures among infants following CPB in the absence of deep hypothermic cardiac arrest and to identify additional risk factors for seizures via a prediction model.

Methods: A retrospective chart review was completed of all consecutive infants ≤ 3 months who received screening EEG following CPB at a single center within a 2-year period during 2017-2019. Clinical and laboratory data were collected from the perioperative period. A prediction model for seizure risk was fit using a random forest algorithm, and receiver operator characteristics were assessed to classify predictions. Fisher's exact test and the logrank test were used to evaluate associations between clinical outcomes and EEG seizures.

Results: A total of 112 infants were included. Seizure incidence was 10.7%. Median time to first seizure was 28.1 h (interquartile range 18.9-32.2 h). The most important factors in predicting seizure risk from the random forest analysis included postoperative neuromuscular blockade, prematurity, delayed sternal closure, bypass time, and critical illness preoperatively. When variables captured during the EEG recording were included, abnormal postoperative neuroimaging and peak lactate were also highly predictive. Overall model accuracy was 90.2%; accounting for class imbalance, the model had excellent sensitivity and specificity (1.00 and 0.89, respectively).

Conclusions: Seizure incidence was similar to recent estimates even in the absence of deep hypothermic cardiac arrest. By employing random forest analysis, we were able to identify novel risk factors for postoperative seizure in this population and generate a robust model of seizure risk. Further work to validate our model in an external population is needed.
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http://dx.doi.org/10.1007/s12028-021-01313-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318326PMC
July 2021

Commentary: A new option for patch material on coronary artery ostium plasty.

JTCVS Tech 2020 Dec 15;4:235-236. Epub 2020 Sep 15.

Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.

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http://dx.doi.org/10.1016/j.xjtc.2020.08.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306519PMC
December 2020

Marijuana Use and the Risk of Early Ischemic Stroke: The Stroke Prevention in Young Adults Study.

Stroke 2021 Oct 16;52(10):3184-3190. Epub 2021 Jul 16.

Department of Neurology (T.D., O.T., H.L., N.F., M.J.S., S.C., C.C., P.M., J.R.N.G., M.P., M.W., S.J.K., J.W.C.), University of Maryland School of Medicine, Baltimore.

Background And Purpose: Few studies have examined the dose-response and temporal relationships between marijuana use and ischemic stroke while controlling for important confounders, including the amount of tobacco smoking. The purpose of our study was to address these knowledge gaps.

Methods: A population-based case-control study with 1090 cases and 1152 controls was used to investigate the relationship of marijuana use and early-onset ischemic stroke. Cases were first-ever ischemic stroke between the ages of 15 and 49 identified from 59 hospitals in the Baltimore-Washington region. Controls obtained by random digit dialing from the same geographic region were frequency-matched to cases by age, sex, region of residence and, except for the initial study phase, race. After excluding subjects with cocaine and other vasoactive substance use, the final study sample consisted of 751 cases and 813 controls. All participants underwent standardized interviews to characterize stroke risk factors and marijuana use. Unconditional logistic regression analysis was used to assess the relationships between marijuana use and risk of ischemic stroke, adjusting for age, sex, race, study phase, the amount of current tobacco smoking, current alcohol use, hypertension, and diabetes.

Results: After adjusting for other risk factors, including the amount of current tobacco smoking, marijuana use was not associated with ischemic stroke, regardless of the timing of use in relationship to the stroke, including ever use, use within 30 days, and use within 24 hours. There was a nonsignificant trend towards increased stroke risk among those who smoked marijuana at least once a week (odds ratio, 1.9 [95% CI, 0.8-4.9]).

Conclusions: These analyses do not demonstrate an association between marijuana use and an increased risk of early-onset ischemic stroke, although statistical power was limited for assessing the association among very heavy users.
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http://dx.doi.org/10.1161/STROKEAHA.120.032811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478805PMC
October 2021

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

PLoS One 2021 2;16(7):e0253611. Epub 2021 Jul 2.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253404PMC
July 2021

Relationship between Posture and Non-Contact Lower Limb Injury in Young Male Amateur Football Players: A Prospective Cohort Study.

Int J Environ Res Public Health 2021 06 14;18(12). Epub 2021 Jun 14.

Priority Research Centre for Physical Activity and Nutrition, The University of Newcastle, Callaghan, NSW 2308, Australia.

Posture, a potentially modifiable injury risk factor, is considered important in injury screening/prevention in athletes, yet few studies investigate relationships between posture and injury. This prospective cohort study investigated whether static posture is associated with lower limb injury risk in male football players ( = 263). Nine aspects of static standing posture (left and right rearfoot, knee interspace, lateral knee, lumbar lordosis, thoracic kyphosis, scoliosis S and C, forward head) were assessed from photographs during the pre-season using the modified Watson and Mac Donncha scale, which was dichotomised for analysis (deviated or normal). Player characteristics (age, height, mass, body mass index, competition level), match/training exposure, and previous and in-season non-contact lower limb injuries were recorded. Binary logistic regression investigated relationships between posture and injury (previous and in-season). Eighty previous and 24 in-season lower limb injuries were recorded. Previous injury was not associated with any postural variable. In-season injury was associated with previous injury (OR = 3.04, 95% CI 1.20-7.68, = 0.02) and having a normal thoracic curve compared to kyphosis (OR = 0.38, 95% CI 0.15-1.00, = 0.05) but no other postural variables. Static postural deviations observed in male football players in the pre-season are not typically associated with non-contact lower limb injury risk; thus, they are unlikely to add value to pre-season screening programs.
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http://dx.doi.org/10.3390/ijerph18126424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296252PMC
June 2021

Genome sequencing unveils a regulatory landscape of platelet reactivity.

Nat Commun 2021 06 15;12(1):3626. Epub 2021 Jun 15.

Division of Intramural Research, Population Sciences Branch, National Heart, Lung and Blood Institute, Bethesda, MD, USA.

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
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http://dx.doi.org/10.1038/s41467-021-23470-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206369PMC
June 2021

Lessons learnt during the COVID-19 pandemic: Why Australian schools should be prioritised to stay open.

J Paediatr Child Health 2021 09 8;57(9):1362-1369. Epub 2021 Jun 8.

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

In 2020, school and early childhood educational centre (ECEC) closures affected over 1.5 billion school-aged children globally as part of the COVID-19 pandemic response. Attendance at school and access to ECEC is critical to a child's learning, well-being and health. School closures increase inequities by disproportionately affecting vulnerable children. Here, we summarise the role of children and adolescents in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and that of schools and ECECs in community transmission and describe the Australian experience. In Australia, most SARS-CoV-2 cases in schools were solitary (77% in NSW and 67% in Victoria); of those that did progress to an outbreak, >90% involved fewer than 10 cases. Australian and global experience has demonstrated that SARS-CoV-2 is predominantly introduced into schools and ECECs during periods of heightened community transmission. Implementation of public health mitigation strategies, including effective testing, tracing and isolation of contacts, means schools and ECECs can be safe, not drivers of transmission. Schools and ECEC are essential services and so they should be prioritised to stay open for face-to-face learning. This is particularly critical as we continue to manage the next phase of the COVID-19 pandemic.
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http://dx.doi.org/10.1111/jpc.15588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242752PMC
September 2021

Increasing awareness and uptake of the MenB vaccine on a large university campus.

Hum Vaccin Immunother 2021 09 2;17(9):3239-3246. Epub 2021 Jun 2.

Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, USA.

: At a large public university, we aimed to evaluate an intervention designed to increase serogroup B meningococcal (MenB) vaccine uptake and awareness. Using a pretest-posttest design with a double posttest, we evaluated an intervention conducted by a local foundation and the Florida Department of Health that distributed MenB vaccine on campus and conducted an educational campaign. Prior to intervention activities, we recruited students to complete a survey about their MenB knowledge and attitudes. For survey participants who provided contact information, we sent two follow-up surveys and assessed MenB vaccine records. We used chi-square tests, adjusted for nonindependence, to compare preintervention to postintervention (three-month and one-year) vaccination and attitudes. Among the 686 students with accessible vaccine records, MenB vaccine initiation increased 9% (from 24% to 33%) and completion increased 8% (from 13% to 21%) from before the intervention to one year after the intervention. When restricting to students who completed the relevant follow-up surveys, the percentage of students who heard of the MenB vaccine increased by 15% ( > .001) from before the intervention to three months after (n = 188 students) and maintained a 10% increase ( > .001) one year after the intervention (n = 261 students). Among students that heard of the MenB vaccine, the percentage of students who thought they needed the MenB vaccine even though they received the MenACWY increased 14% ( = .03) by the three-month postintervention survey and up to 18% by the one-year follow-up ( = .002). A university-wide, on-campus vaccination and educational campaign increased college students' MenB vaccine initiation, completion, and knowledge.: NCT02975596.
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http://dx.doi.org/10.1080/21645515.2021.1923347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381836PMC
September 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Kawasaki Disease Complicated by Coinfection.

Case Rep Pediatr 2021 2;2021:5584514. Epub 2021 Apr 2.

University of Florida Shands Children's Hospital, Department of Pediatric Hospital Medicine, Gainesville, FL, USA.

Kawasaki disease is a medium vessel vasculitis with a multisystem presentation affecting 9-20 per 100,000 children under 5 years of age in the United States. coinfection has not been previously described. We present a 12-month-old vaccinated male with Kawasaki disease in the setting of bacteremia. Initial intervention for the Kawasaki disease with IVIG was ineffective, prompting adjunctive therapy with anakinra, with eventual full recovery. Concurrent Kawasaki disease and bacteremia may confound diagnosis and necessitate nontraditional treatment approaches.
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http://dx.doi.org/10.1155/2021/5584514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055415PMC
April 2021

Compassionate Deactivation of Pediatric Ventricular Assist Devices: A Review of 14 Cases.

J Pain Symptom Manage 2021 09 25;62(3):523-528. Epub 2021 Apr 25.

Department of Anesthesia, Stanford University School of Medicine (D.C.), Palo Alto, California, USA.

Context: Compassionate deactivation (CD) of ventricular assist device (VAD) support is a recognized option for children when the burden of therapy outweighs the benefits.

Objectives: To describe the prevalence, indications, and outcomes of CD of children supported by VADs at the end of life.

Methods: Review of cases of CD at our institution between 2011 and 2020. To distinguish CD from other situations where VAD support is discontinued, patients were excluded from the study if they died during resuscitation (including extracorporeal membrane oxygenation), experienced brain or circulatory death prior to deactivation, or experienced a non-survivable brain injury likely to result in imminent death regardless of VAD status.

Results: Of 24 deaths on VAD, 14 (58%) were CD. Median age was 5.7 (interquartile range (IQR) 0.6, 11.6) years; 6 (43%) had congenital heart disease; 4 (29%) were on a device that can be used outside of the hospital. CD occurred after 40 (IQR: 26, 75) days of support; none while active transplant candidates. CD discussions were initiated by the caregiver in 6 (43%) cases, with the remainder initiated by a medical provider. Reasons for CD were multifactorial, including end-organ injury, infection, and stroke. CD occurred with endotracheal extubation and/or discontinuation of inotropes in 12 (86%) cases, and death occurred within 10 (IQR: 4, 23) minutes of CD.

Conclusion: CD is the mode of death in more than half of our VAD non-survivors and is pursued for reasons primarily related to noncardiac events. Caregivers and providers both initiate CD discussions. Ventilatory and inotropic support is often withdrawn at time of CD with ensuing death.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.01.125DOI Listing
September 2021

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Am J Hum Genet 2021 05 21;108(5):874-893. Epub 2021 Apr 21.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206199PMC
May 2021

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Hum Mol Genet 2021 Jul;30(15):1443-1456

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
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http://dx.doi.org/10.1093/hmg/ddab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283205PMC
July 2021

Engineering High-Yield Biopolymer Secretion Creates an Extracellular Protein Matrix for Living Materials.

mSystems 2021 Mar 23;6(2). Epub 2021 Mar 23.

Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, USA

The bacterial extracellular matrix forms autonomously, giving rise to complex material properties and multicellular behaviors. Synthetic matrix analogues can replicate these functions but require exogenously added material or have limited programmability. Here, we design a two-strain bacterial system that self-synthesizes and structures a synthetic extracellular matrix of proteins. We engineered to secrete an extracellular matrix protein composed of an elastin-like polypeptide (ELP) hydrogel fused to supercharged SpyCatcher [SC]. This biopolymer was secreted at levels of 60 mg/liter, an unprecedented level of biomaterial secretion by a native type I secretion apparatus. The ELP domain was swapped with either a cross-linkable variant of ELP or a resilin-like polypeptide, demonstrating this system is flexible. The SC-ELP matrix protein bound specifically and covalently to the cell surface of a strain that displays a high-density array of SpyTag (ST) peptides via its engineered surface layer. Our work develops protein design guidelines for type I secretion in and demonstrates the autonomous secretion and assembly of programmable extracellular protein matrices, offering a path forward toward the formation of cohesive engineered living materials. Engineered living materials (ELM) aim to mimic characteristics of natural occurring systems, bringing the benefits of self-healing, synthesis, autonomous assembly, and responsiveness to traditional materials. Previous research has shown the potential of replicating the bacterial extracellular matrix (ECM) to mimic biofilms. However, these efforts require energy-intensive processing or have limited tunability. We propose a bacterially synthesized system that manipulates the protein content of the ECM, allowing for programmable interactions and autonomous material formation. To achieve this, we engineered a two-strain system to secrete a synthetic extracellular protein matrix (sEPM). This work is a step toward understanding the necessary parameters to engineering living cells to autonomously construct ELMs.
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http://dx.doi.org/10.1128/mSystems.00903-20DOI Listing
March 2021

Barriers and facilitators to pre-exposure prophylaxis among African migrants in high income countries: a systematic review.

Sex Health 2021 May;18(2):130-139

Department of Infectious Diseases, The Alfred and Central Clinical School, Monash University, Melbourne, Vic., Australia; and Burnet Institute, Melbourne, Vic., Australia; and Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Vic., Australia.

Background The aim of this review is to explore acceptability, barriers, and facilitators to PrEP use among African migrants in high-income countries.

Methods: A systematic review was conducted to explore reasons that contribute to low PrEP uptake in this population. Three online databases, abstracts from key conferences and reference lists of relevant studies articles published between the 2 July 2018 and 3 March 2019 were searched. Narrative synthesis was performed on quantitative data and thematic synthesis was performed on qualitative data.

Results: Of 1779 titles retrieved, two cross-sectional studies (United States (US) (n = 1), United Kingdom (UK) (n = 1)) and six qualitative studies (US (n = 2), UK (n = 3), Australia (n = 1)) met inclusion criteria. PrEP acceptability was reported in one cross-sectional article and two qualitative articles. Cross-sectional studies measured acceptability and willingness to use PrEP; in one study, 46% of African migrant men found PrEP use acceptable, and following PrEP education, another study categorised 60% of participants as willing to use PrEP if it were cost-free. Qualitative studies reported mixed acceptability, with higher acceptability reported for serodiscordant couples. Barriers and facilitators to PrEP use were coded into five themes: cultural aspects of stigma; knowledge gap in health literacy; risks unrelated to HIV transmission; practical considerations for PrEP use; and the impact of PrEP use on serodiscordant couples.

Conclusions: Several common barriers to PrEP use, including stigma, health literacy and risk perception and cost, were identified. Findings were limited by there being no published data on uptake. Additional work is needed to understand PrEP acceptability and uptake among African migrants.
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http://dx.doi.org/10.1071/SH20175DOI Listing
May 2021

COVID-19, children and schools: overlooked and at risk.

Med J Aust 2021 03;214(4):189-189.e1

Murdoch Children's Research Institute, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.50936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013862PMC
March 2021

Heterozygosity for a Pathogenic Variant in That Causes Autosomal Recessive Gitelman Syndrome Is Associated with Lower Serum Potassium.

J Am Soc Nephrol 2021 03 4;32(3):756-765. Epub 2021 Feb 4.

Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Background: Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known.

Methods: A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake.

Results: A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G ) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers.

Conclusions: This study provides evidence that heterozygosity for a pathogenic variant in causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.
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http://dx.doi.org/10.1681/ASN.2020071030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920171PMC
March 2021

Mid-Term Outcomes After Unifocalization Guided by Intraoperative Pulmonary Flow Study.

World J Pediatr Congenit Heart Surg 2021 Jan;12(1):76-83

Department of Cardiothoracic Surgery, 24349Lucile Packard Children's Hospital Heart Center, Stanford University School of Medicine, Palo Alto, CA, USA.

Background: Repair of tetralogy of Fallot (TOF) with major aortopulmonary collateral arteries (MAPCAs) requires unifocalization of pulmonary circulation, intracardiac repair with the closure of the ventricular septal defect, and placement of a right ventricle (RV) to pulmonary artery (PA) conduit. The decision to perform complete repair is sometimes aided by an intraoperative flow study to estimate the total resistance of the reconstructed pulmonary circulation.

Methods: We reviewed patients who underwent unifocalization and PA reconstruction for TOF/MAPCAs to evaluate acute and mid-term outcomes after repair with and without flow studies and to characterize the relationship between PA pressure during the flow study and postrepair RV pressure.

Results: Among 579 patients who underwent unifocalization and PA reconstruction for TOF/MAPCAs, 99 (17%) had an intraoperative flow study during one (n = 91) or more (n = 8) operations to determine the suitability for a complete repair. There was a reasonably good correlation between mean PA pressure at 3 L/min/m during the flow study and postrepair RV pressure and RV:aortic pressure ratio. Acute and mid-term outcomes (median: 3.8 years) after complete repair in the flow study patients (n = 78) did not differ significantly from those in whom the flow study was not performed (n = 444). Furthermore, prior failed flow study was not associated with differences in outcome after subsequent intracardiac repair.

Conclusions: The intraoperative flow study remains a useful adjunct for determining the suitability for complete repair in a subset of patients undergoing surgery for TOF/MAPCAs, as it is reasonably accurate for estimating postoperative PA pressure and serves as a reliable guide for the feasibility of single-stage complete repair.
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http://dx.doi.org/10.1177/2150135120964427DOI Listing
January 2021

Perceptions and Knowledge About the MenB Vaccine Among Parents of High School Students.

J Community Health 2021 08 2;46(4):808-816. Epub 2021 Jan 2.

Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, USA.

Serogroup B meningococcal disease (MenB) causes almost 60% of meningitis cases among adolescents and young adults. Yet, MenB vaccine coverage among adolescents remains below 10%. Since parents are the primary medical decision makers for adolescents, we examined MenB vaccination rates and parent attitudes about meningitis and the MenB vaccine. In 2018, in conjunction with a county-wide, school-based immunization campaign, we conducted a mixed methods study among parents of 16- to 17-year-olds. We facilitated focus groups asking parents about their knowledge of meningitis and reactions to educational materials and sent behavioral surveys based on Health Belief Model constructs to parents through the county high school system. Parents in three focus groups (n = 8; participation rate = 13%) expressed confusion about their child's need to receive the MenB vaccine in addition to the meningococcal conjugate vaccine (MenACWY), but conveyed strong trust in their physicians' recommendation. Among survey participants (n = 170), 70 (41%) had heard of the MenB vaccine. Among those 70 parents, the most common barriers to vaccination were concerns about side effects (55%) and uncertainty of susceptibility due to receipt of the MenACWY vaccine (30%). The percentage of teens that received at least one dose of the MenB vaccine was 50% (n = 35) by parent report and 23% (n = 16) by state vaccination records. Parents demonstrated uncertainty and confusion about the MenB vaccine particularly due to the existence of another meningitis vaccine and limited health care provider recommendations. Confirmatory studies of parent confusion about the MenB vaccine are needed to develop interventions.
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http://dx.doi.org/10.1007/s10900-020-00954-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316167PMC
August 2021

Effects of the BDNF Val66Met polymorphism on functional status and disability in young stroke patients.

PLoS One 2020 11;15(12):e0237033. Epub 2020 Dec 11.

University of Maryland School of Medicine, Baltimore, MD, United States of America.

Background And Purpose: The preponderance of evidence from recent studies in human subjects supports a negative effect of the BDNF Val66Met polymorphism on motor outcomes and motor recovery. However prior studies have generally reported the effect of the Met allele in older stroke patients, while potential effects in younger stroke patients have remained essentially unexamined. The lack of research in younger patients is significant since aging effects on CNS repair and functional recovery after stroke are known to interact with the effects of genetic polymorphisms. Here we present a study of first-ever ischemic stroke patients aged 15-49 years that examines the effect of Met carrier status on functional disability.

Methods: 829 patients with a first ischemic stroke (Average age = 41.4 years, SD = 6.9) were recruited from the Baltimore-Washington region. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Our sample contained 165 Met carriers and 664 non-Met carriers. Modified Rankin scores as recorded at discharge were obtained from the hospital records by study personnel blinded to genotype, and binarized into "Good" versus "Poor" outcomes (mRS 0-2 vs. 3+), with mRS scores 3+ reflecting a degree of disability that causes loss of independence.

Results: Our analysis showed that the Met allele conveyed a proportionally greater risk for poor outcomes and disability-related loss of independence with mRS scores 3+ (adjusted OR 1.73, 95% CI 1.13-2.64, p = 0.01).

Conclusions: The BDNF Val66Met polymorphism was negatively associated with functional outcomes at discharge in our sample of 829 young stroke patients. This finding stands in contrast to what would be predicted under the tenets of the resource modulation hypothesis (i.e. that younger patients would be spared from the negative effect of the Met allele on recovery since it is posited to arise as a manifestation of age-related decline in physiologic resources).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732081PMC
January 2021

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

J Clin Endocrinol Metab 2021 01;106(2):372-387

Brigham and Women's Hospital, Havard University, Boston, MA, USA.

Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation.

Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease.

Design: Genetics of Obesity-associated Liver Disease Consortium.

Setting: Population-based.

Main Outcome: Computed tomography measured liver attenuation.

Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate.

Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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http://dx.doi.org/10.1210/clinem/dgaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823249PMC
January 2021

and Long QT Syndrome in 1/45 Amish: The Road From Identification to Implementation of Culturally Appropriate Precision Medicine.

Circ Genom Precis Med 2020 12 3;13(6):e003133. Epub 2020 Nov 3.

Regeneron Genetics Center LLC, Tarrytown, NY (C.V.H., N.G., C.G.-J., A.E., A.R.S.).

Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health.

Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting.

Results: A missense variant was identified in (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram (=5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, =0.0006), greater history of syncope (32% versus 17%, =0.020), and higher rate of sudden cardiac death in first degree relatives
Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.
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http://dx.doi.org/10.1161/CIRCGEN.120.003133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748050PMC
December 2020
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