دورية أكاديمية
أعرض في EDS

Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival.

التفاصيل البيبلوغرافية
العنوان: Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival.
المؤلفون: Sun Z; Division of Nephrology, Department of Medicine., Zhang Z; Department of Genetics and Genomic Science, and.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Banu K; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Gibson IW; Max Rady college of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada., Colvin RB; Harvard Medical school, Boston, Massachusetts, USA., Yi Z; Division of Nephrology, Department of Medicine., Zhang W; Division of Nephrology, Department of Medicine., De Kumar B; Yale Center for Genomics, New Haven, Connecticut, USA., Reghuvaran A; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Pell J; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Manes TD; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Djamali A; Maine Medical Center, Portland, Maine, USA., Gallon L; Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., O'Connell PJ; The Westmead Institute for Medical Research, University of Sydney, New South Wales, Australia., He JC; Division of Nephrology, Department of Medicine., Pober JS; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Heeger PS; Cedars-Sinai Medical Center, Los Angeles, California, USA., Menon MC; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2023 Nov 01; Vol. 133 (21). Date of Electronic Publication: 2023 Nov 01.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Kidney Transplantation*, Humans ; Transforming Growth Factor beta1/genetics ; Graft Rejection/genetics ; Kidney ; Tissue Donors ; HLA Antigens ; Graft Survival/genetics ; Membrane Proteins ; Adaptor Proteins, Signal Transducing/genetics ; LIM Domain Proteins/genetics
مستخلص: 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.
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معلومات مُعتمدة: R24 AI108564 United States AI NIAID NIH HHS; U01 AI063594 United States AI NIAID NIH HHS; R01 DK122164 United States DK NIDDK NIH HHS; R21 AI178705 United States AI NIAID NIH HHS; U01 AI070107 United States AI NIAID NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; R01 DK132274 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: Adaptive immunity; Genetic variation; Genetics; Organ transplantation; Transplantation
المشرفين على المادة: 0 (Transforming Growth Factor beta1)
0 (HLA Antigens)
0 (LIMS1 protein, human)
0 (Membrane Proteins)
0 (Adaptor Proteins, Signal Transducing)
0 (LIM Domain Proteins)
تواريخ الأحداث: Date Created: 20230907 Date Completed: 20231102 Latest Revision: 20240313
رمز التحديث: 20240313
مُعرف محوري في PubMed: PMC10617779
DOI: 10.1172/JCI170420
PMID: 37676733
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI170420