Quantifying donor-recipient mismatches using recipient-derived sources of donor DNA

Area of Science:

• Genetics
• Immunology
• Transplantation

Background:

• Non-HLA donor-recipient (D-R) genetic mismatches are implicated in kidney allograft injury and graft loss.
• Clinical assessment of these mismatches is hindered by the lack of donor DNA post-transplantation.

Purpose of the Study:

• To evaluate if recipient-derived samples can infer donor genotype and D-R mismatches non-invasively.
• To assess the efficacy of urine cell-pellet DNA (U-DNA) compared to plasma cell-free DNA (cfDNA) for inferring D-R mismatches.

Main Methods:

• Whole-exome sequencing of donor and recipient genomic DNA (g-DNA).
• Targeted sequencing of 55 non-HLA genes with customized intronic probes.
• Comparison of D-R mismatches inferred from recipient U-DNA and cfDNA against donor g-DNA.

Main Results:

• U-DNA significantly outperformed cfDNA in identifying D-R mismatches across various genomic scales (P<0.001).
• U-DNA successfully identified gene-level mismatches in LIMS1 and inferred known risk alleles like SHROOM3 and APOL1.
• Mismatch scores were generated for genome-wide, exonic, and non-synonymous exonic mismatches.

Conclusions:

• Urine cell-pellet DNA, combined with recipient genome analysis, can non-invasively infer relevant non-HLA loci and mismatches.
• This approach circumvents the necessity for donor genomic DNA, offering a practical clinical tool.
• Demonstrates proof-of-concept for non-invasive genetic mismatch assessment in kidney transplantation.