Evidence map›Paper›PMID 38789639›Full record

ArticleJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology2024

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV.

Cagla Akay-Espinoza, Sarah E B Newton, Beth A Dombroski, Asha Kallianpur, Ajay Bharti, Donald R Franklin, Gerard D Schellenberg, Robert K Heaton, Igor Grant, Ronald J Ellis and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Cagla Akay-EspinozaDepartment of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA.
Sarah E B NewtonDepartment of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA.
Beth A DombroskiDepartment of Pathology and Laboratory Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Asha KallianpurGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Ajay BhartiDepartments of Medicine, University of California, San Diego, CA, USA.
Donald R FranklinDepartment of Psychiatry, University of California, San Diego, CA, USA.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Robert K HeatonDepartment of Psychiatry, University of California, San Diego, CA, USA.
Igor GrantDepartment of Psychiatry, University of California, San Diego, CA, USA.
Ronald J EllisDepartment of Psychiatry, University of California, San Diego, CA, USA.
Scott L LetendreDepartment of Psychiatry, University of California, San Diego, CA, USA.
Kelly L Jordan-SciuttoDepartment of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA. jordank@upenn.edu.

Funding

STRUCTURAL NEUROIMAGING COREP30MH062512 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Jessica Lynette Montoya · 2001 to 2026
$50.4M
Penn Mental Health AIDS Research CenterP30MH097488 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI Karine Dube, Kelly L Jordan-Sciutto · 2013 to 2026
$23.5M
Impact of coding and non-coding variation in progressive supranuclear palsyUG3NS104095 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DICKSON, DENNIS WILLIAM, GESCHWIND, DANIEL H · 2017 to 2019
$3.6M
Role of PERK haplotypes in HIV-Associated Neurocognitive DisordersR01MH109382 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI JORDAN-SCIUTTO, KELLY L · 2016 to 2020
$3.1M
Iron and Mitochondrial Genomics in Neuro-inflammation and HAND: A CHARTER StudyR01MH095621 · NIMH · VANDERBILT UNIVERSITY MEDICAL CENTER · PI HULGAN, TODD M, KALLIANPUR, ASHA R · 2011 to 2015
$3.1M
Iron Dysregulation and Neuropsychiatric Complications of HIV Across the Lifespan: Impact of Biologic Factors, Antiretroviral Therapy and GeneticsR01MH124530 · NIMH · CLEVELAND CLINIC LERNER COM-CWRU · PI KALLIANPUR, ASHA R · 2021 to 2025
$2.4M
CNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH /CHARTER/ -278022005-278022005N01MH022005 · NIMH · UNIVERSITY OF CA -SAN DIEGO · PI GRANT, IGOR · 2003 to 2006
–
NIH HHS MH095621NIH HHS MH109382NIH HHS MH22005NIH HHS UG3NS104095NIMH NIH HHS HHSN271201000030CNIMH NIH HHS HHSN271201000036CNIMH NIH HHS N01 MH022005NIMH NIH HHS P30 MH062512NIMH NIH HHS P30 MH097488NIMH NIH HHS R01 MH095621NIMH NIH HHS R01 MH109382NIMH NIH HHS R01 MH124530NINDS NIH HHS UG3 NS104095
6 · The paper itself

Abstract

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4 + T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p < 0.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (p < 0.001) and more NCI (p < 0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value > 13 were independently associated with GDS and NCI (p < 0.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but present in multivariable analyses, raising the possibility of specific SNVs in EIF2AK3 as an important component of genetic vulnerability to neurocognitive complications in PWH.

Indexed as

eIF-2 KinaseHIV InfectionsPolymorphism, Single NucleotideAdultCognitive DysfunctionCohort StudiesFemaleHumansMaleMiddle AgedRetrospective StudiesEIF2AK3 protein, humaneIF-2 KinaseEIF2AK3HaplotypeHIVIntegrated stress responseNeurocognitive impairmentSingle nucleotide variant

Identifiers

PMID38789639
PMCPMC11126443

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.