Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival
Zeguo Sun, … , Peter S. Heeger, Madhav C. Menon
Zeguo Sun, … , Peter S. Heeger, Madhav C. Menon
Published September 7, 2023
Citation Information: J Clin Invest. 2023;133(21):e170420. https://doi.org/10.1172/JCI170420.
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Research Article Genetics

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

Abstract

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.

Authors

Zeguo Sun, Zhongyang Zhang, Khadija Banu, Ian W. Gibson, Robert B. Colvin, Zhengzi Yi, Weijia Zhang, Bony De Kumar, Anand Reghuvaran, John Pell, Thomas D. Manes, Arjang Djamali, Lorenzo Gallon, Philip J. O’Connell, John Cijiang He, Jordan S. Pober, Peter S. Heeger, Madhav C. Menon

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Figure 3

Genome-wide screening of D-R mismatch at gene level revealed the association of mismatch score at LIMS1 locus with graft loss.

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Genome-wide screening of D-R mismatch at gene level revealed the associa...
(A) A representative Manhattan plot shows the P values of the association of gene-level “any mismatch” scores, with DCGL in GoCAR being 1 out of the 4 models tested (see B below). The 23 top candidate gene loci that were commonly identified from 4 different analyses are highlighted by red diamonds and included GCC2 and LIMS1. (B) Venn diagram shows the number of genes identified with mismatch score at the LIMS1 locus in significant association with DCGL (nominal P ≤ 0.01) from 4 different analyses: double mismatch or any mismatch (definition in Figure 1 and Methods) for the whole GoCAR cohort or the subset of European-to-European (E-to-E) D-R pairs. (C and D) Kaplan-Meier plots show the graft survival curves for equally dichotomized groups of mismatch scores at the LIMS1 locus, where mismatch scores were defined as “any mismatch” (C) and “double mismatch” (D). P values were derived from log-rank tests in comparison of upper quantile versus lower quantile.