TY - JOUR
T1 - Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans
AU - Lee, Sulggi A.
AU - Mefford, Joel A.
AU - Huang, Yong
AU - Witte, John S.
AU - Martin, Jeffrey N.
AU - Haas, David W.
AU - McLaren, Paul J.
AU - Mushiroda, Taisei
AU - Kubo, Michiaki
AU - Byakwaga, Helen
AU - Hunt, Peter W.
AU - Kroetz, Deanna L.
N1 - Funding Information:
This work was supported in part by the National Institutes of Health (R56AI100765, R21AI078774, K24MH087227, T32AA007240, R01MH054907 UM1CA181255, P30AI27763, P01AI076174, and U01GM061390), the Doris Duke Charitable Foundation (P.W.H., Clinical Scientist Development Award 2008047), the Sullivan Family Foundation, HIV Translational Research Training Grant (T32AI060530) (S.A.L.), a Center for AIDS Research HIV Mentored Scientist Award (S.A.L.), Bristol-Myers Squibb Virology Fellowship Award (S.A.L.), and the NIH Pharmacogenomics Research Network-RIKEN Center for Genomic Medicine Global Alliance.
Publisher Copyright:
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2016/7/17
Y1 - 2016/7/17
N2 - 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/μl, 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 × 10 -5). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 × 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-γ, TNF-α, 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. ©
AB - 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/μl, 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 × 10 -5). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 × 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-γ, TNF-α, 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. ©
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U2 - 10.1097/QAD.0000000000001124
DO - 10.1097/QAD.0000000000001124
M3 - Article
C2 - 27088321
AN - SCOPUS:84963978909
VL - 30
SP - 1807
EP - 1815
JO - AIDS
JF - AIDS
SN - 0269-9370
IS - 11
ER -