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 2

Genome-wide D-R mismatch score was associated with graft loss.

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Genome-wide D-R mismatch score was associated with graft loss. Genome-wi...
Genome-wide mismatch score between donor-recipient (D-R) pairs was calculated at all imputed SNPs with high confidence after quality control, and normalized by IQR. The distribution of normalized genome-wide mismatch scores is shown for D-R pairs stratified by different combinations of D-R genetic ancestries in GoCAR (A) and CTOT (C), with inter-ancestry D-R pairs in red and intra-ancestry in blue. Genome-wide D-R mismatch score is highly correlated with interpersonal relatedness, reflected as the proportion of identity-by-descent (pIBD) in GoCAR (B) and CTOT (D). (E) Forest plots show the association with DCGL of genome-wide D-R mismatch scores calculated at all imputed SNPs as well as the SNPs within exonic and non-exonic regions. The association analyses were performed using univariate and multivariable Cox regression models adjusted for HLA mismatches, induction therapy, and donor status for both the GoCAR and CTOT cohorts.