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Observational Study
. 2015 Nov 1;61(9):1476-84.
doi: 10.1093/cid/civ527. Epub 2015 Jun 30.

Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection

Todd Hulgan  1 , David C Samuels  1 , William Bush  1 , Ronald J Ellis  2 , Scott L Letendre  2 , Robert K Heaton  2 , Donald R Franklin  2 , Peter Straub  1 , Deborah G Murdock  1 , David B Clifford  3 , Ann C Collier  4 , Benjamin B Gelman  5 , Christina M Marra  4 , Justin C McArthur  6 , J Allen McCutchan  2 , Susan Morgello  7 , David M Simpson  7 , Igor Grant  2 , Asha R Kallianpur  8 ; CHARTER Group
Collaborators, Affiliations
Observational Study

Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection

Todd Hulgan et al. Clin Infect Dis. .

Abstract

Background: Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort.

Methods: CHARTER is an observational study of ambulatory HIV-infected adults. Haplogroups were assigned using mtDNA sequence, and principal components were derived from ancestry-informative nuclear DNA variants. Outcomes were cross-sectional global deficit score (GDS) as a continuous measure, GDS impairment (GDS ≥ 0.50), and HIV-associated neurocognitive disorder (HAND) using international criteria. Multivariable models were adjusted for comorbidity status (incidental vs contributing), current CART, plasma HIV RNA, reading ability, and CD4 cell nadir.

Results: Haplogroups were available from 1027 persons; median age 43 years, median CD4 nadir 178 cells/mm(3), 72% on CART, and 46% with HAND. The 102 (9.9%) persons of genetically determined admixed Hispanic ancestry had more impairment by GDS or HAND than persons of European or African ancestry (P < .001 for all). In multivariate models including persons of admixed Hispanic ancestry, those with haplogroup B had lower GDS (β = -0.34; P = .008) and less GDS impairment (odds ratio = 0.16; 95% confidence interval, .04, .63; P = .009) than other haplogroups. There were no significant haplogroup associations among persons of European or African ancestry.

Conclusions: In these mostly CART-treated persons, mtDNA haplogroup B was associated with less NCI among persons of genetically determined Hispanic ancestry. mtDNA variation may represent an ancestry-specific factor influencing NCI in HIV-infected persons.

Keywords: AIDS; DNA, mitochondrial; HIV; cognitive disorders.

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Figures

Figure 1.
Figure 1.
Box and dotplots of global deficit scores among participants of African (panel A), European (panel B), and Hispanic (panel C) ancestry, by major mtDNA haplogroups. Boxes denote median and interquartile range; whiskers denote 95th percentiles. P-value = .002 by univariate linear regression for haplogroup B vs other haplogroups among the admixed Hispanic population in Panel C. Abbreviation: mtDNA, mitochondrial DNA.
Figure 2.
Figure 2.
Bar graphs of percentage of participants with global deficit score (GDS) impairment (GDS ≥ 0.50; panel A) and HIV-associated neurocognitive disorder (HAND) of any severity (panel B), by ancestry and major mtDNA haplogroups. Error bars for frequency estimates were calculated as 2 × Standard Error. P-values from univariate logistic regression models are shown. Abbreviations: HIV, human immunodeficiency virus; mtDNA, mitochondrial DNA; NS, not significant.
See this image and copyright information in PMC

References

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