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 Transplantation

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 5

Dosage effect and directionality of the haplotype mismatch associated with DCGL.

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Dosage effect and directionality of the haplotype mismatch associated wi...
Kaplan-Meier survival curves of DCGL grouped by the dosage of mismatches (i.e., the number of “alien” alleles introduced by the donor) at the haplotype in all (A) and European-to-European (E-to-E) D-R pairs (B). Kaplan-Meier survival curves of DCGL grouped by the directionality of the mismatches at the haplotype and the rs893403 risk mismatch in all (C) and E-to-E D-R pairs (D). Major: mismatch derived from major haplotype allele introduced by donor to the recipient with homozygous minor allele and no rs893403 risk mismatch; Minor: mismatch derived from minor haplotype allele introduced by donor to the recipient with homozygous major allele and no rs893403 risk mismatch; rs893403: mismatch at rs893403 defined as risk allele (A allele) introduced by donor to the recipient carrying G/G genotype; Other: no mismatch at the haplotype and rs893403.