Kidney transplantation recipients face rejection despite anti-rejection drugs and matching efforts. Biopsy confirmed acute rejection (AR) and chronic allograft nephropathy (CAN) are 2 rejection phenotypes of interest. We conducted a genome-wide association study (GWAS) in European-derived kidney transplant donors and recipients. Well-functioning transplant donors (TX; N=261) were compared to AR (N=90) or CAN (N=105) participants. The same comparisons were conducted in recipients (TX N=226; AR N=71; CAN N=105). Analyses were adjusted for multiple comparisons and additionally for population substructure by including the first 2 multi-dimensional scaling dimension values as covariates in logistic regression. The most significant findings were identified in the TX vs. CAN tests (lowest unadjusted P=6.51E-08), which also displayed the largest odds ratios, and the least significant findings were identified for the TX vs. AR tests. Results need to be validated in an independent collection.
Proportion of identity by state, pi-hat, was calculated between donor-recipient pairs and compared between different donor-types and also by outcome (TX, AR, CAN). No significant difference within donor-type matched pairs was observed between outcome phenotypes in European-derived samples.
A set of primers was developed to sequence 112 candidate genes for AR and CAN. A custom resequencing tiling array was designed and tested. Technological development in the field called for testing the same panel on next-generation sequencing technology. We improved quality control metrics by trimming the reads and successfully called single nucleotide polymorphisms (SNPs) at a rate of 1/1000 bases sequenced.
Finally, TNFAIP3, a candidate gene for autoimmune disease (AID) was sequenced in samples multiply affected with AID (N=123) and in controls (N=397). One novel intronic insertion/deletion polymorphism was significantly associated with multiple AID diagnoses (Fisher’s Exact P-value=0.0090; OR (95% CI) 7.053(1.67-29.79). Coding polymorphism rs2230926 was tested for association in a panel of individuals from families with multiple AIDs. Significant association was observed with all affected individuals (P=0.0336) as well as psoriasis, Crohn’s disease and rheumatoid arthritis, with marginal association for Sjogren’s and Graves disease. Additionally, we conducted an association study of the entire gene locus in lupus and identified 3 independent signals of association, including coding SNP rs2230926.
|Commitee:||Criswell, Lindsey A., Hamilton, Steven P.|
|School:||University of California, San Francisco|
|Department:||Pharmaceutical Sciences and Pharmacogenomics|
|School Location:||United States -- California|
|Source:||DAI-B 71/05, Dissertation Abstracts International|
|Keywords:||Acute rejection, Autoimmune disease, Chronic allograft nephropathy, Genome-wide association study, Kidney transplantation|
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