Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Sulggi A. Lee, Joel A. Mefford, Yong Huang, John S. Witte, Jeffrey N. Martin, David W. Haas, Paul J. McLaren, Taisei Mushiroda, Michiaki Kubo, Helen Byakwaga, Peter W. Hunt, Deanna L. Kroetz

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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. ©

Original languageEnglish
Pages (from-to)1807-1815
Number of pages9
JournalAIDS
Volume30
Issue number11
DOIs
Publication statusPublished - 17-07-2016

Fingerprint

Kynurenine
Tryptophan
Indoleamine-Pyrrole 2,3,-Dioxygenase
HIV
Genome
Single Nucleotide Polymorphism
Play Therapy
Exome
Protein Tyrosine Phosphatases
Mortality
Toll-Like Receptors
CD4 Lymphocyte Count
Vitamin D
African Americans
Genes
HIV-1
Monocytes
Linear Models
Therapeutics
Biomarkers

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Lee, S. A., Mefford, J. A., Huang, Y., Witte, J. S., Martin, J. N., Haas, D. W., ... Kroetz, D. L. (2016). Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans. AIDS, 30(11), 1807-1815. https://doi.org/10.1097/QAD.0000000000001124
Lee, Sulggi A. ; Mefford, Joel A. ; Huang, Yong ; Witte, John S. ; Martin, Jeffrey N. ; Haas, David W. ; McLaren, Paul J. ; Mushiroda, Taisei ; Kubo, Michiaki ; Byakwaga, Helen ; Hunt, Peter W. ; Kroetz, Deanna L. / Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans. In: AIDS. 2016 ; Vol. 30, No. 11. pp. 1807-1815.
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abstract = "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. {\circledC}",
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Lee, SA, Mefford, JA, Huang, Y, Witte, JS, Martin, JN, Haas, DW, McLaren, PJ, Mushiroda, T, Kubo, M, Byakwaga, H, Hunt, PW & Kroetz, DL 2016, 'Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans', AIDS, vol. 30, no. 11, pp. 1807-1815. https://doi.org/10.1097/QAD.0000000000001124

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans. / Lee, Sulggi A.; Mefford, Joel A.; Huang, Yong; Witte, John S.; Martin, Jeffrey N.; Haas, David W.; McLaren, Paul J.; Mushiroda, Taisei; Kubo, Michiaki; Byakwaga, Helen; Hunt, Peter W.; Kroetz, Deanna L.

In: AIDS, Vol. 30, No. 11, 17.07.2016, p. 1807-1815.

Research output: Contribution to journalArticle

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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.

PY - 2016/7/17

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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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