Polymorphisms in CAMKK2 associate with susceptibility to sensory neuropathy in HIV patients treated without stavudine.

Abstract

HIV-associated sensory neuropathy (HIV-SN) is a debilitating neurological complication of HIV infection potentiated by the antiretroviral drug stavudine. While stavudine is no longer used, HIV-SN now affects around 15% of HIV+ Indonesians. Here, we investigate whether polymorphisms within the P2X-block (P2X4R, P2X7R, CAMKK2) and/or ANAPC5 mark susceptibility to HIV-SN in this setting. As polymorphisms in these genes associated with HIV-SN in African HIV patients receiving stavudine, the comparison can identify mechanisms independent of stavudine. HIV patients who had never used stavudine (n = 202) attending clinics in Jakarta were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Open-array technology was used to type 48 polymorphisms spanning the four genes. Haplotypes were derived for each gene using fastPHASE. Haplogroups were constructed with median-joining methods. Multivariable models optimally predicting HIV-SN were based on factors achieving p < 0.2 in bivariate analyses. Minor alleles of three co-inherited polymorphisms in CAMKK2 (rs7975295*C, rs1560568*A, rs1132780*T) associated with a reduced prevalence of HIV-SN individually and after adjusting for lower CD4 T cell count and viremia (p = 0.0002, pseudo R2 = 0.11). The optimal model for haplotypes linked HIV-SN with viremia and lower current CD4 T cell count, plus CAMKK2 haplotypes 6 and 11 and P2X7R haplotypes 2 and 12 (p = 0.0002; pseudo R2 = 0.11). CAMKK2 haplogroup A (includes 16 haplotypes and all instances of rs7975295*C, rs1560568*A, rs1132780*T) associated with reduced rates of HIV-SN (p = 0.02, OR = 0.43 CI = 0.21-0.88). These findings support a protective role for these three alleles, suggesting a role in the pathogenesis of HIV-SN that is independent of stavudine.

• Authors: Jessica Gaff, Fitri Octaviana, Ibnu Ariyanto, Catherine Cherry, Simon M Laws, Patricia Price
• Journal: Journal of neurovirology (J Neurovirol) Vol. 25 Issue 6 Pg. 814-824 (12 2019) ISSN: 1538-2443 [Electronic] United States
• PMID: 31309408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Stavudine
• CAMKK2 protein, human
• Calcium-Calmodulin-Dependent Protein Kinase Kinase

Topics

• Adult
• Anti-HIV Agents (adverse effects)
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (genetics)
• Female
• Genetic Predisposition to Disease (genetics)
• HIV Infections (complications, drug therapy)
• Humans
• Male
• Middle Aged
• Peripheral Nervous System Diseases (epidemiology, genetics, virology)
• Polymorphism, Single Nucleotide
• Prevalence
• Stavudine (adverse effects)