Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival
Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1-dependent effects on T cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
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| Enthalten in: |
The Journal of clinical investigation - 133(2023), 21 vom: 01. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Zeguo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.11.2023 Date Revised 13.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI170420 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM36174370X |
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| 100 | 1 | |a Sun, Zeguo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 02.11.2023 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1-dependent effects on T cells | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Adaptive immunity | |
| 650 | 4 | |a Genetic variation | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Organ transplantation | |
| 650 | 4 | |a Transplantation | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 650 | 7 | |a HLA Antigens |2 NLM | |
| 650 | 7 | |a LIMS1 protein, human |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a LIM Domain Proteins |2 NLM | |
| 700 | 1 | |a Zhang, Zhongyang |e verfasserin |4 aut | |
| 700 | 1 | |a Banu, Khadija |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, Ian W |e verfasserin |4 aut | |
| 700 | 1 | |a Colvin, Robert B |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Zhengzi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Weijia |e verfasserin |4 aut | |
| 700 | 1 | |a De Kumar, Bony |e verfasserin |4 aut | |
| 700 | 1 | |a Reghuvaran, Anand |e verfasserin |4 aut | |
| 700 | 1 | |a Pell, John |e verfasserin |4 aut | |
| 700 | 1 | |a Manes, Thomas D |e verfasserin |4 aut | |
| 700 | 1 | |a Djamali, Arjang |e verfasserin |4 aut | |
| 700 | 1 | |a Gallon, Lorenzo |e verfasserin |4 aut | |
| 700 | 1 | |a O'Connell, Philip J |e verfasserin |4 aut | |
| 700 | 1 | |a He, John Cijiang |e verfasserin |4 aut | |
| 700 | 1 | |a Pober, Jordan S |e verfasserin |4 aut | |
| 700 | 1 | |a Heeger, Peter S |e verfasserin |4 aut | |
| 700 | 1 | |a Menon, Madhav C |e verfasserin |4 aut | |
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