Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy

Kallianpur, Asha R.; Jia, Peilin; Ellis, Ronald J.; Zhao, Zhongming; Bloss, Cinnamon S.; Wen, Wanqing; Marra, Christina M.; Hulgan, Todd; Simpson, David M.; Morgello, Susan; McArthur, Justin C.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; McCutchan, J. Allen; Franklin, Donald; Samuels, David C.; Rosario, Debralee; Holzinger, Emily R.; Murdock, Deborah G.; Letendre, Scott; Grant, Igor

doi:10.1371/journal.pone.0103123

Cited by 30 publications

(30 citation statements)

References 81 publications

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“…However, these incidences of PSN have been inevitable because of the widespread clinical applications of NRTIs. Recent findings have established a link between genetic variation in iron-metabolism and PSN in HIV +ve patients on cART treatment [39]. They have found that polymorphisms in transferrin, transferrin receptor, bone morphogenetic protein 6, aconitase 1, solute carrier family 11 member 2, and frataxin genes confer reduced risk; other variants of transferrin,aconitase 1, bone morphogenetic protein 6, beta-2-microglobulin, and ceruloplasmin genes confer increased risk to peripheral neuropathy.…”

Section: Neuro-muscular Complications In Hiv-associated Sensory Neuromentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

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Section: Neuro-muscular Complications In Hiv-associated Sensory Neuromentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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“…Iron-related genes have been previously implicated in neurological complications of HIV infection in our studies [Kallianpur and others 2014]. We also evaluated 20 iron-related candidate genes noted to be of interest previously [Kallianpur and others 2014] as part of a nested candidate-gene analysis, based on their direct or indirect roles in iron metabolism, transport, storage, and/or regulation, and on the existence of prevalent SNPs in these genes.…”

Section: Resultsmentioning

confidence: 99%

“…We also evaluated 20 iron-related candidate genes noted to be of interest previously [Kallianpur and others 2014] as part of a nested candidate-gene analysis, based on their direct or indirect roles in iron metabolism, transport, storage, and/or regulation, and on the existence of prevalent SNPs in these genes. We examined the association of these iron-metabolism-related SNPs with GDS (Table 5).…”

Section: Resultsmentioning

confidence: 99%

“…Variants in genes regulating multiple biological processes may impact the risk of NCI, progression of HAND, and response to ART. Candidate-gene association studies [Bol and others 2012; Burt and others 2008] and a single published genome-wide association study (GWAS) [Levine and others 2012] revealed promising genetic variants associated with HAND, including variants in immune-related genes [Pemberton and others 2008], ion channel transporters [Kallianpur and others 2014], and genes related to nuclear and mitochondrial DNA damage [Kallianpur and Levine 2014]. However, most of these associations failed to reach genome-wide statistical significance and have either not been subjected to independent replication attempts, or have not been successfully replicated in subsequent studies, due at least in part to phenotypic and population differences between studies.…”

Section: Introductionmentioning

confidence: 99%

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Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

Jia

Zhao

Hulgan

et al. 2017

American J of Med Genetics Pt B

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HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS≥0.5 and 684 controls with GDS<0.5, and GDS as a continuous variable) and Frascati HAND definitions that incorporate assessment of functional impairment by self-report and performance-based criteria. Genotype data was obtained using the Affymetrix Human SNP Array 6.0 platform. Multivariable logistic or linear regression-based association tests were performed for GDS-defined NCI and HAND. GWAS results did not reveal SNPs meeting the genome-wide significance threshold (5.0×10−8) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (p=8.1×10−7) and rs11681615 (1.2×10−6), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (p=1.3×10−7) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (p≤2.9×10−6). This GWAS, conducted among ART-era participants from a single cohort with robust neurological phenotyping, suggests roles for several biologically plausible loci in HAND that deserve further exploration.

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“…Population stratification was evaluated by adjustment for four principal components variables representing ancestry-related genetic information, which were generated from genome-wide genotype data in CHARTER (African, European, Hispanic, and other), consistent with previous published studies (Kallianpur et al, 2014; Hulgan et al, 2015). Genetic ancestry has been advocated to use in genetics studies instead of race/ethnicity, since the latter is a socio-cultural category that does not fully capture the genetic variation and its influence on biological outcomes such as those considered in this study (Fujimura & Rajagopalan, 2011; Brummel et al, 2015; Mersha & Abebe, 2015).…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein E ε4 genotype status is not associated with neuroimaging outcomes in a large cohort of HIV+ individuals

et al. 2016

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Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in HIV-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes) and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM) and basal ganglia) were examined. Secondary analyses explored this relationship separately in individuals ≥ 50 years old (n= 173) and < 50 years old (n=63). No significant differences were observed between ApoE ε4+ (ApoE ε3/ε4 & ApoE ε4/ε4) individuals (n=69) and ApoE ε4- (ApoE ε2/ε3 & ApoE ε3/ε3) individuals (n=167). When individuals were further divided by age, no significant genotype group differences were identified in individuals < 50 or ≥ 50 years of age on any neuroimaging outcome. The ApoE ε4 allele did not affect brain integrity in this large, diverse sample of HIV+ individuals. The effects of ApoE ε4 may not be apparent until more advanced ages, and may be more prominent when present along with other risk factors for neuronal damage.

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Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy

Cited by 30 publications

References 81 publications

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

Apolipoprotein E ε4 genotype status is not associated with neuroimaging outcomes in a large cohort of HIV+ individuals

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