Publication Abstract Display
Type: Published Abstract
Title: Nuclear-mitochondrial interactions and neurocognitive impairment in HIV+ adults.
Authors: Smieszek S, Kallianpur A, Samuels D, Franklin D, Heaton R, Letendre S, Ellis R, Hulgan T, Bush W
Year: 2017
Publication: Annual Conference on Retroviruses and Opportunistic Infections
Volume: Issue: Pages:
Abstract:Background HIV-Associated Neurocognitive Disorder (HAND) is a term that captures a wide spectrum of neurocognitive deficits, ranging from mild to severe, in HIV-infected persons. The genetic underpinnings of this complex phenotype are incompletely understood. Abnormalities of mitochondrial function and iron metabolism have long been implicated in neurodegeneration. In this analysis, we aimed to characterize the mitochondrial DNA (mtDNA) haplogroup interactions with nuclear genes found to be associated with HAND phenotypes. Methods Genetic associations with HAND were investigated in the CHARTER cohort, encompassing 1025 individuals of African, admixed Hispanic and European ancestry. CHARTER is a U.S.-based observational study of neuro-HIV outcomes in ambulatory, HIV+ adults who underwent standardized, comprehensive NC assessment (2003-7) and were assigned a Global Deficit Score (GDS) [normal (GDS<0.5) or impaired (GDS≥0.5)]. We employed a polygenic modeling approach to investigate the global effect of previously associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. Subsequently, we performed interaction analysis per SNP by mtDNA haplogroup combination, adjusting for population effects and known clinical covariates (comorbidity status, current CART use, plasma viral load, nadir CD4+ T-cell count). Results We found evidence of interactions between nuclear genomic SNPs en masse and mtDNA haplogroups within European and African-ancestry individuals, as shown in Table 1. The analysis of each SNP by mtDNA haplogroup combination identified significant interactions between a region of chromosome 19 (two strongly correlated SNPs, rs17160128 and rs12460243) and European mtDNA haplogroups in HAND, with the SNPs showing a more dominant association in H and J haplogroups versus a more additive association in T and UK haplogroups. Conclusions: These associations highlight the potential role of FBN3, a nearby gene that belongs to the fibrillin gene family. Fibrillins are extracellular matrix molecules, which assemble into microfibrils in many connective tissues and are important in regulating pathways of the immune response, inflammation and are involved in maintenance of blood-brain-barrier integrity. These findings were demonstrated using a novel analytic approach and indicate a new potential genetic mechanism in the pathogenesis of HAND, which may lead to greater understanding of the pathophysiology of this neurocognitive disorder.

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