Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population

Shevchenko, Andrey; Zhernakova, Daria V.; Malov, Sergey V.; Komissarov, Alexey; Kolchanova, Sofia M.; Tamazian, Gaik; Antonik, Alexey; Cherkasov, Nikolay; Kliver, Sergey; Rotkevich, Mikhail; Evsyukov, Igor; Vlahov, David; Thami, Prisca K; Gaseitsiwe, Simani; Novitsky, Vladimir; Essex, Myron; O’Brien, Stephen J.

doi:10.1073/pnas.2107830118

Cited by 3 publications

(3 citation statements)

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“…Nonetheless, the study has some limitations. However, it should be noted that our focus is on deleterious variants and variation among HIV-1 positive and negative individuals and not on the genetic susceptibility or association studies of HIV-1 in Botswana as previously reported ( Xie et al, 2017 ; Shevchenko et al, 2021 ). Also, the sample size is relatively modest and larger sample sizes would probably yield more findings.…”

Section: Discussionmentioning

confidence: 99%

“…In summary, we reported a WGS study as part of ongoing and recent study ( Shevchenko et al, 2021 ) on clinical phenotypes of HIV-1 in Africa. Notably, we generated a catalogue of candidate modifier genes and their associated pathways that clustered in pathophysiological pathways important in HIV-1 and with implications for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

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Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes

Thami,

Choga,

Dandara

et al. 2023

Front. Genet.

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HIV infection continues to be a major global public health issue. The population heterogeneity in susceptibility or resistance to HIV-1 and progression upon infection is attributable to, among other factors, host genetic variation. Therefore, identifying population-specific variation and genetic modifiers of HIV infectivity can catapult the invention of effective strategies against HIV-1 in African populations. Here, we investigated whole genome sequences of 390 unrelated HIV-positive and -negative individuals from Botswana. We report 27.7 million single nucleotide variations (SNVs) in the complete genomes of Botswana nationals, of which 2.8 million were missing in public databases. Our population structure analysis revealed a largely homogenous structure in the Botswana population. Admixture analysis showed elevated components shared between the Botswana population and the Niger-Congo (65.9%), Khoe-San (32.9%), and Europeans (1.1%) ancestries in the population of Botswana. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated. The most deleterious variants were enriched in five genes: ACTRT2 (the Actin Related Protein T2), HOXD12 (homeobox D12), ABCB5 (ATP binding cassette subfamily B member 5), ATP8B4 (ATPase phospholipid transporting 8B4) and ABCC12 (ATP Binding Cassette Subfamily C Member 12). These genes are enriched in the glycolysis and gluconeogenesis (p < 2.84e-6) pathways and therefore, may contribute to the emerging field of immunometabolism in which therapy against HIV-1 infection is being evaluated. Published transcriptomic evidence supports the role of the glycolysis/gluconeogenesis pathways in the regulation of susceptibility to HIV, and that cumulative effects of genetic modifiers in glycolysis/gluconeogenesis pathways may potentially have effects on the expression and clinical variability of HIV-1. Identified genes and pathways provide novel avenues for other interventions, with the potential for informing the design of new therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes

Thami,

Choga,

Dandara

et al. 2023

Front. Genet.

Self Cite

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“…Moreover, one should keep an open eye for a connection of PTPRA variants with other pathologies as well. As an example we mention its recently suggested ties with HIV-1C acquisition and pathogenesis ( Shevchenko et al, 2021 ), although the small size of the studied cohort implies the need for follow-up studies on PTPRA as a determinant in viral transmitted diseases.…”

Section: Documented Genetic Variabilitymentioning

confidence: 99%

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

Hendriks

Cruchten

Pulido

2023

Front. Cell Dev. Biol.

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Protein tyrosine phosphatases, together with protein tyrosine kinases, control many molecular signaling steps that control life at cellular and organismal levels. Impairing alterations in the genes encoding the involved proteins is expected to profoundly affect the quality of life—if compatible with life at all. Here, we review the current knowledge on the effects of germline variants that have been reported for genes encoding a subset of the protein tyrosine phosphatase superfamily; that of the thirty seven classical members. The conclusion must be that the newest genome research tools produced an avalanche of data that suggest ‘guilt by association’ for individual genes to specific disorders. Future research should face the challenge to investigate these accusations thoroughly and convincingly, to reach a mature genotype-phenotype map for this intriguing protein family.

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Legacy of a magic gene— CCR5- ∆ 32 : From discovery to clinical benefit in a generation

OBrien

2024

Proc. Natl. Acad. Sci. U.S.A.

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The discovery of the 32-bp deletion allele of the chemokine receptor gene CCR5 showed that homozygous carriers display near-complete resistance to HIV infection, irrespective of exposure. Algorithms of molecular evolutionary theory suggested that the CCR5- ∆ 32 mutation occurred but once in the last millennium and rose by strong selective pressure relatively recently to a ~10% allele frequency in Europeans. Several lines of evidence support the hypothesis that CCR5- ∆ 32 was selected due to its protective influence to resist Yersinia pestis, the agent of the Black Death/bubonic plague of the 14th century. Powerful anti-AIDS entry inhibitors targeting CCR5 were developed as a treatment for HIV patients, particularly those whose systems had developed resistance to powerful anti-retroviral therapies. Homozygous CCR5- ∆ 32/ ∆ 32 stem cell transplant donors were used to produce HIV-cleared AIDS patients in at least five “cures” of HIV infection. CCR5 has also been implicated in regulating infection with Staphylococcus aureus , in recovery from stroke, and in ablation of the fatal graft versus host disease (GVHD) in cancer transplant patients. While homozygous CCR5- ∆ 32/32 carriers block HIV infection, alternatively they display an increased risk for encephalomyelitis and death when infected with the West Nile virus.

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Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population

Cited by 3 publications

References 75 publications

Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes

Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

Legacy of a magic gene— CCR5- ∆ 32 : From discovery to clinical benefit in a generation

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