Journal
AIDS
Volume 30, Issue 11, Pages 1807-1815Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000001124
Keywords
antiretroviral therapy; genome-wide association study; HIV; kynurenine; tryptophan
Categories
Funding
- National Institutes of Health [R56AI100765, R21AI078774, K24MH087227, T32AA007240, R01MH054907, UM1CA181255, P30AI27763, P01AI076174, U01GM061390]
- Doris Duke Charitable Foundation [2008047]
- Sullivan Family Foundation
- HIV Translational Research Training Grant [T32AI060530]
- Center for AIDS Research HIV Mentored Scientist Award
- Bristol-Myers Squibb Virology Fellowship Award
- NIH Pharmacogenomics Research Network-RIKEN Center for Genomic Medicine Global Alliance
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Objective: Plasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans. Design/methods: We performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log(10) kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry. Results: Among 597 Ugandans, 62% were woman, median age was 35, median baseline CD4(+) cell count was 135 cells/mu l, and median baseline HIV-1 RNA was 5.1 log(10) copies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log(10) kynurenine/tryptophan ratio (P < 5.0 x 10(-5)). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 x 10(-7)), including genes encoding protein tyrosine phosphatases (PTPRM and PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these single nucleotide polymorphisms were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small US cohort (N = 262; 33% African-American). Conclusion: Our findings highlight a potentially important role of IFN-gamma, TNF-alpha, and Toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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