Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection

Overview

Journal Clin Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2015 Jul 2

PMID 26129753

Citations 23

Authors

Todd Hulgan

David C Samuels

William Bush

Ronald J Ellis

Scott L Letendre

Robert K Heaton

Donald R Franklin

Peter Straub

Deborah G Murdock

David B Clifford

Ann C Collier

Benjamin B Gelman

Christina M Marra

Justin C McArthur

J Allen McCutchan

Susan Morgello

David M Simpson

Igor Grant

Asha R Kallianpur

Affiliations

Soon will be listed here.

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.

Citing Articles

Association between a lower T-CD4+ /CD8+ lymphocyte ratio and cognitive impairment in older persons with HIV.

Ruiz-Manriquez C, Avila-Funes J, Branas F, Crabtree-Ramirez B, Amieva H, Hernandez-Ruiz V Eur Geriatr Med. 2024; 16(1):305-313.

PMID: 39476100 DOI: 10.1007/s41999-024-01079-7.

Relationships of mitochondrial DNA mutations and select clinical diagnoses in perinatally HIV- and ART-exposed uninfected children.

Gojanovich G, Marsit C, Kacanek D, Russell J, Hudson G, Van Dyke R Mitochondrion. 2024; 79:101949.

PMID: 39218053 PMC: 11568920. DOI: 10.1016/j.mito.2024.101949.

Disparities in Metabolic Syndrome and Neurocognitive Function Among Older Hispanics/Latinos with Human Immunodeficiency Virus.

Marquine M, Kamalyan L, Zlatar Z, Yassai-Gonzalez D, Perez-Tejada A, Umlauf A AIDS Patient Care STDS. 2024; 38(5):195-205.

PMID: 38662469 PMC: 11301713. DOI: 10.1089/apc.2024.0043.

Mitochondrial DNA mutation pathogenicity score and neurocognitive performance in persons with HIV.

Volpe K, Samuels D, Elson J, Steyn J, Gebretsadik T, Ellis R Mitochondrion. 2023; 74:101820.

PMID: 37989461 PMC: 10872545. DOI: 10.1016/j.mito.2023.11.003.

Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management.

Ellis R, Marquine M, Kaul M, Fields J, Schlachetzki J Nat Rev Neurol. 2023; 19(11):668-687.

PMID: 37816937 PMC: 11052664. DOI: 10.1038/s41582-023-00879-y.

References

Guardado-Estrada M, Medina-Martinez I, Juarez-Torres E, Roman-Bassaure E, Macias L, Alfaro A . The Amerindian mtDNA haplogroup B2 enhances the risk of HPV for cervical cancer: de-regulation of mitochondrial genes may be involved. J Hum Genet. 2012; 57(4):269-76. DOI: 10.1038/jhg.2012.17. View

Mancuso M, Filosto M, Orsucci D, Siciliano G . Mitochondrial DNA sequence variation and neurodegeneration. Hum Genomics. 2009; 3(1):71-8. PMC: 3525185. DOI: 10.1186/1479-7364-3-1-71. View

Tiao M, Liou C, Huang L, Wang P, Lin T, Chen J . Associations of mitochondrial haplogroups b4 and e with biliary atresia and differential susceptibility to hydrophobic bile Acid. PLoS Genet. 2013; 9(8):e1003696. PMC: 3744426. DOI: 10.1371/journal.pgen.1003696. View

Grant I, Franklin Jr D, Deutsch R, Woods S, Vaida F, Ellis R . Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014; 82(23):2055-62. PMC: 4118496. DOI: 10.1212/WNL.0000000000000492. View

Casaletto K, Umlauf A, Beaumont J, Gershon R, Slotkin J, Akshoomoff N . Demographically Corrected Normative Standards for the English Version of the NIH Toolbox Cognition Battery. J Int Neuropsychol Soc. 2015; 21(5):378-91. PMC: 4490030. DOI: 10.1017/S1355617715000351. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Bi R, Zhang W, Yu D, Li X, Wang H, Hu Q . Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese. Neurobiol Aging. 2014; 36(3):1604.e7-16. DOI: 10.1016/j.neurobiolaging.2014.10.009. View

van Rij R, Portegies P, Hallaby T, Lange J, Visser J, de Roda Husman A . Reduced prevalence of the CCR5 delta32 heterozygous genotype in human immunodeficiency virus-infected individuals with AIDS dementia complex. J Infect Dis. 1999; 180(3):854-7. DOI: 10.1086/314940. View

Corder E, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J . HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998; 4(10):1182-4. DOI: 10.1038/2677. View

10.

Kallianpur A, Levine A . Host genetic factors predisposing to HIV-associated neurocognitive disorder. Curr HIV/AIDS Rep. 2014; 11(3):336-52. PMC: 4121535. DOI: 10.1007/s11904-014-0222-z. View

11.

Wallace D . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39:359-407. PMC: 2821041. DOI: 10.1146/annurev.genet.39.110304.095751. View

12.

Panos S, Hinkin C, Singer E, Thames A, Patel S, Sinsheimer J . Apolipoprotein-E genotype and human immunodeficiency virus-associated neurocognitive disorder: the modulating effects of older age and disease severity. Neurobehav HIV Med. 2015; 5:11-22. PMC: 4659385. DOI: 10.2147/NBHIV.S39573. View

13.

Levran O, Awolesi O, Shen P, Adelson M, Kreek M . Estimating ancestral proportions in a multi-ethnic US sample: implications for studies of admixed populations. Hum Genomics. 2012; 6:2. PMC: 3437566. DOI: 10.1186/1479-7364-6-2. View

14.

Hall J, Dumitrescu L, Dilks H, Crawford D, Bush W . Accuracy of administratively-assigned ancestry for diverse populations in an electronic medical record-linked biobank. PLoS One. 2014; 9(6):e99161. PMC: 4045967. DOI: 10.1371/journal.pone.0099161. View

15.

Morgan E, Woods S, Letendre S, Franklin D, Bloss C, Goate A . Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders. J Neurovirol. 2013; 19(2):150-6. PMC: 3668779. DOI: 10.1007/s13365-013-0152-3. View

16.

Allard M, Polanskey D, Wilson M, Monson K, Budowle B . Evaluation of variation in control region sequences for Hispanic individuals in the SWGDAM mtDNA data set. J Forensic Sci. 2006; 51(3):566-73. DOI: 10.1111/j.1556-4029.2006.00136.x. View

17.

Xie H, Perin J, Schurr T, Dulik M, Zhadanov S, Baur J . Mitochondrial genome sequence analysis: a custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy. BMC Bioinformatics. 2011; 12:402. PMC: 3234255. DOI: 10.1186/1471-2105-12-402. View

18.

Trudler D, Nash Y, Frenkel D . New insights on Parkinson's disease genes: the link between mitochondria impairment and neuroinflammation. J Neural Transm (Vienna). 2015; 122(10):1409-19. DOI: 10.1007/s00702-015-1399-z. View

19.

Kenney M, Chwa M, Atilano S, Falatoonzadeh P, Ramirez C, Malik D . Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions. Hum Mol Genet. 2014; 23(13):3537-51. PMC: 4049308. DOI: 10.1093/hmg/ddu065. View

20.

Kloss-Brandstatter A, Pacher D, Schonherr S, Weissensteiner H, Binna R, Specht G . HaploGrep: a fast and reliable algorithm for automatic classification of mitochondrial DNA haplogroups. Hum Mutat. 2010; 32(1):25-32. DOI: 10.1002/humu.21382. View