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 - 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.
UR - https://www.scopus.com/pages/publications/84963978909
UR - https://www.scopus.com/pages/publications/84963978909#tab=citedBy
U2 - 10.1097/QAD.0000000000001124
DO - 10.1097/QAD.0000000000001124
M3 - Article
C2 - 27088321
AN - SCOPUS:84963978909
SN - 0269-9370
VL - 30
SP - 1807
EP - 1815
JO - AIDS
JF - AIDS
IS - 11
ER -
