The role of CAMKK2 polymorphisms in HIV-associated sensory neuropathy in South Africans

Gaff, Jessica; Pillay, Prinisha; Cherry, Catherine L.; Laws, Simon M.; Price, Patricia; Kamerman, Peter R.

doi:10.1016/j.jns.2020.116987

Cited by 7 publications

(12 citation statements)

References 43 publications

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“…rs208307 associated with higher Z-scores in memory and executive domain optimal models at multiple timepoints. This allele was linked with HIV-SN in Africans treated with stavudine but not in Africans and Indonesians treated without stavudine ( Gaff et al., 2019 , Gaff et al., 2020 ; Goullee et al., 2016 ). rs208307 is located at an acceptor splice site in intron 6 and is associated with altered expression and splicing of P2X7R in the GTEx Portal ( https://gtexportal.org/ ).…”

Section: Discussionmentioning

confidence: 89%

“…The gene encoding P2X7R ( P2X7R ) is highly polymorphic and located in a region of high linkage disequilibrium (LD) on chromosome 12. We have associated single nucleotide polymorphisms (SNP) and haplotypes within P2X7R with HIV-associated sensory neuropathy (a common neurological complication of HIV infection affecting peripheral nerves) in Indonesians and Africans ( Gaff et al., 2019 , Gaff et al., 2020 ; Goullee et al., 2016 , Safri et al., 2020 ). Furthermore, SNP in P2X7R have been associated with neuroinflammatory and neuropsychological conditions including bipolar disorder, multiple sclerosis, and Alzheimer’s disease ( Sanz et al., 2014 ; Oyanguren-Desez et al., 2011 ; McQuillin et al., 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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Neurocognitive outcomes in indonesians living with HIV are influenced by polymorphisms in the gene encoding purinergic P2X receptor 7

Gaff

Estiasari

Diafiri

et al. 2021

Brain, Behavior, & Immunity - Health

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The advent of effective antiretroviral therapy (ART) has decreased the prevalence and severity of HIV-associated neurocognitive disorders (HAND), but milder forms of HAND remain despite optimal treatment. Neuronal injury and loss due to inflammation may mediate HAND. P2X7R encodes purinergic P2X receptor 7 which influences neuroinflammatory pathways and carries polymorphisms associated with sensory neuropathy in HIV patients. We assessed associations between P2X7R polymorphisms and neurocognitive outcomes in Indonesian patients (n = 59) as they commenced ART and after 3, 6 and 12 months. Z-scores were calculated over 5 domains using local controls and evaluated as continuous variables. Optimal linear regression models identified polymorphisms influencing attention, memory, executive function, motor speed and total cognitive function at each time point. rs504677 was associated with lower executive and motor speed Z-scores at 0, 3, 6, and 12 months, and with memory at 0 and 12 months. Memory was positively influenced by carriage of the rs208296 minor allele at 0, 3 and 6 months and by carriage of the rs208307 minor allele at 0 and 12 months. Higher attention Z-scores associated with carriage of minor alleles of rs1653598 after 0 and 12 months. These also positively influenced executive function and motor speed after 0–6 months. This study identifies polymorphisms in P2X7R which influence domain-specific neurocognitive outcomes in HIV+ Indonesians prior to and shortly after commencing ART. This implicates purinergic P2X receptor 7 in the pathogenesis of HAND.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Neurocognitive outcomes in indonesians living with HIV are influenced by polymorphisms in the gene encoding purinergic P2X receptor 7

Gaff

Estiasari

Diafiri

et al. 2021

Brain, Behavior, & Immunity - Health

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“…Mutations of mtDNA have been implicated as the inciting event in the idiosyncratic neuropathy induced by ART [ 20 ]. One particular SNP, called calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) has been associated with a higher risk of developing HIV-SN in South-African HIV patients [ 21 , 22 ]. In the study by Goullee et al, several haplotypes and SNP were identified in patients with HIV in black South-African patients and the gene CAMKK2 was exhibited as a significant predictor of HIV-SN susceptibility in patients independent of stavudine exposure [ 21 ].…”

Section: Reviewmentioning

confidence: 99%

Neuropathy in Human Immunodeficiency Virus: A Review of the Underlying Pathogenesis and Treatment

Motwani¹,

Asif²,

Patel³

et al. 2022

Cureus

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This article explores the various causes of the human immunodeficiency virus (HIV), and its associated neuropathy, including the effects of HIV on the nervous system and the long-standing therapy that is often provided to patients with HIV. Several studies regarding the neurotoxic effects of combined antiretroviral therapy (cART) and HIV were reviewed and various hypotheses were discussed. Furthermore, we present the nature of HIV-sensory neuropathy (HIV-SN) among different demographic populations and their subsequent risk factors predisposing them to this condition. It was observed that the incidence of the disease increases in increased survival of the patients as well as in males. Finally, the current approach to HIV-SN and its overlapping features with other causes of peripheral neuropathy have been discussed which demonstrates that a clinical examination is the most important clue for a healthcare professional to suspect the disease. Our main aim was to study the current perspectives and guidelines for diagnosing and managing a patient with HIV-SN to reduce disease prevalence and bring about a more aware frame of mind when following up with an HIV patient.

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“…Genetic studies of other P2X4R SNP in larger cohorts should consider ethnicity because we have shown that this has clear effects on linkage disequilibrium influencing the haplotypes that predominate in the populations. 14,16,17 Fluency and Executive Function Domain Zscores were Influenced by SNP in CAMKK2…”

Section: P2x4r Snps Were Not Retained In Linear Regression Modelsmentioning

confidence: 99%

“…rs2686344 associated with lower rates of peripheral neuropathy in Africans treated with stavudine but showed no effect in Africans and Indonesians treated without stavudine. 14,16,17 Stavudine probably inhibits mitochondrial function in peripheral nerves, so the ART regimen may be important. We sought validation of associations between rs2686344 and cognitive deficits in the Australian patients with HIV as described above.…”

Section: P2x4r Snps Were Not Retained In Linear Regression Modelsmentioning

confidence: 99%

Brief Report: Polymorphisms in CAMKK2 may Influence Domain-Specific Neurocognitive Function in HIV+ Indonesians Receiving ART

Gaff

Estiasari

Diafiri

et al. 2022

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background: Despite effective antiretroviral therapy (ART), milder forms of HIV-associated neurocognitive disorders remain prevalent and are characterized by neuroinflammation, synaptic dysfunction, and neuronal loss. Methods:We explore associations between neurocognitive impairment in HIV+ Indonesians and 17 polymorphisms in adjacent genes involved in inflammation and neuronal growth/repair pathways, P2X4R and CAMKK2. HIV+ Indonesians (n = 59) who had received ART for 12 months were assessed to derive Z-scores for the attention, fluency, memory, executive, and motor speed domains relative to local control subjects. These were used to determine total cognitive scores. Results:No alleles of P2X4R displayed significant associations with neurocognition in bivariate or multivariable analyses. In CAMKK2, rs2686344 influenced total cognitive scores in bivariate analyses (P = 0.04). Multivariable linear regression modeling independently associated rs2686344 with higher executive function Z-scores (P = 0.05) after adjusting for CD4 T-cell counts (adjusted R 2 = 0.103, model P = 0.034), whereas rs1653588 associated with lower and rs1718120 (P = 0.05) with higher fluency Z-scores (P = 0.05) after adjusting for education and log 10 HIV RNA copies/mL (adjusted R 2 = 0.268, model P = 0.001).Conclusions: Polymorphisms in CAMKK2 may influence neurocognitive outcomes in specific domains in HIV+ Indonesians receiving ART for 12 months.

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The role of CAMKK2 polymorphisms in HIV-associated sensory neuropathy in South Africans

Cited by 7 publications

References 43 publications

Neurocognitive outcomes in indonesians living with HIV are influenced by polymorphisms in the gene encoding purinergic P2X receptor 7

Neurocognitive outcomes in indonesians living with HIV are influenced by polymorphisms in the gene encoding purinergic P2X receptor 7

Neuropathy in Human Immunodeficiency Virus: A Review of the Underlying Pathogenesis and Treatment

Brief Report: Polymorphisms in CAMKK2 may Influence Domain-Specific Neurocognitive Function in HIV+ Indonesians Receiving ART

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