A Haptoglobin Exon Copy Number Variant Associates With HIV-Associated Neurocognitive Impairment in European and African-Descent Populations.

A common two-exon deletion distinguishes the gene encoding the free hemoglobin capturing protein-haptoglobin (HP)-into two alleles: and . To evaluate the impact of this copy number variant (CNV) on neurocognitive impairment (NCI) in people living with HIV, we imputed this variant in 432 European-descent (EUR) and 491 African-descent (AFR) participants from the CNS HIV Antiretroviral Therapy Effects Research Study using an optimized imputation pipeline and evaluated its associations with NCI. At baseline, in AFR, the allele decreased the odds of NCI (defined by a global deficit score, GDS, ; Odds Ratio, = 0.584, = 0.022). However, in EUR, increased the odds ( = 2.081, = 0.040) of NCI suggesting a detrimental effect. These effects were extended to longitudinal analyses using repeated measurements where the protective effect of the allele in AFR became marginally significant ( = 0.054) and in EUR the detrimental effect increased in significance ( = 0.037). In EUR, the allele slightly reduced the risk of NCI over time ( = 0.028 per allele per year, = 0.024). Further analyses of cognitive domain-specific impairment revealed that the -NCI effect was based on changes in learning, speed of information processing, and verbal domains over time differing by ancestry groups. Overall, these findings suggest that these functional CNV alleles influence the likelihood of NCI and contribute to changes in neurocognitive function over time in people living with HIV.