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

Abstract

A common two-exon deletion distinguishes the gene encoding the free hemoglobin capturing protein—haptoglobin (HP)–into two alleles: HP1 and HP2. 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 HP2 allele decreased the odds of NCI (defined by a global deficit score, GDS, ⩾0.5; Odds Ratio, OR = 0.584, p = 0.022). However, in EUR, HP2 increased the odds (OR = 2.081, p = 0.040) of NCI suggesting a detrimental effect. These effects were extended to longitudinal analyses using repeated measurements where the protective effect of the HP2 allele in AFR became marginally significant (p = 0.054) and in EUR the detrimental effect increased in significance (p = 0.037). In EUR, the HP2 allele slightly reduced the risk of NCI over time (OR = 0.028 per allele per year, p = 0.024). Further analyses of cognitive domain-specific impairment revealed that the HP-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 HP CNV alleles influence the likelihood of NCI and contribute to changes in neurocognitive function over time in people living with HIV.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease

“…Though the hemoglobin binding affinity of the HP protein complex is not strongly influenced, due to their larger sizes, multimers demonstrate reduced binding capability, thereby leading to lower functional activity compared to dimers 22 . This SV has been previously associated with plasma lipid levels, and (in our prior work) with neurocognitive deficits in people living with human immunodeficiency virus (HIV) 20,24,25 . A small study also reported that the interaction of APOE ε4 and HP genotypes associated with longevity in a population in central Italy 26 …”

“…Only imputation dosages ≥0.9 were kept for further analyses and dosages < 0.9 were removed. This approach has been previously validated 25 …”

A Haptoglobin (HP) Structural Variant Alters the Effect of APOE Alleles on Alzheimer’s Disease

“…This approach was validated using gene-tissue expression (GTEx) RNA expression data (Supplemental Text 2, Table S1, S2, Figure S1). To impute the HP SV, we used a customized version of a published imputation reference that was developed using droplet PCR and validated using RNA-sequencing [20], [25], [Supplement File --Imputation Reference]. After TOPMed imputation, we first extracted SNPs that are included in the HP imputation reference.…”

“…Only imputation dosages ≥0.9 were kept for further analyses and dosages <0.9 were removed. This approach has been previously validated [25]. The "N"s are the number of individuals that are included in the analyses after omitting for missing in AD status.…”

“…Though the hemoglobin binding affinity of the HP protein complex is not strongly influenced, due to their larger sizes, multimers demonstrate reduced binding capability, thereby leading to lower functional activity compared to dimers [22]. This SV has been previously associated with plasma lipid levels, and (in our prior work) with neurocognitive deficits in people living with HIV [20], [24], [25]. A small study also reported that the interaction of APOEε4 and HP genotypes associated with longevity in a population in central Italy [26].…”