The genetics of transplantation is unique and fascinating. When a donor organ is placed in the recipient's body, two genomes (each with unique properties) interact under the influence of immunosuppressive agents to produce life-saving results. However, In some cases, the recipient's immune system rejects the foreign organ, leading to the destruction of the donor organ. The success or failure of kidney transplantation is undoubtedly Influenced by genetics. In this project, we propose to pursue the pathways previously discovered to influence kidney transplantation outcome utilizing the newest DNA target capture/sequencing technologies to identify the genetic variations that correlate with acute rejection and chronic rejection (CAN/IFTA with inflammation) in kidney transplants. Taking advantage of the large kidney transplant cohort assembled by our collaborators, we will perform deep DNA sequencing of all human exons and the high value non-coding regions of ~2000 genes in pathways associated with kidney transplantation outcome in 600 donor and recipient DNA samples from subjects with "extreme phenotypes". For example, we will sequence subjects who develop acute rejection or chronic rejection much faster than the average kidney transplant patient. In addition, we will study patients that are >5 years post-transplant and have normal and stable kidney transplant function (sCr <1.5 mg/dl). Variants identified will be validated by Sanger sequencing and their genetic effects studied by typing the variants against a large cohort of kidney transplant patients. The variants that are highly correlated with kidney transplantation outcome and most likely to affect gene expression or gene function will be selected for biological validation In functional studies using freshly purified blood cells from independently collected kidney transplants with the correlative clinical phenotypes.

Public Health Relevance

Recent advances in DNA sequencing technology and the identification of pathways associated with kidney transplantation outcomes provide us with an opportunity to search for the genetic variants that cause acute and chronic rejection in a comprehensive way. If successful, our project will Identify genetic factors that give us insights into the biological basis for graft rejection in kidney transplantation and provide new biomarkers for diagnosis and targets for drug development.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Scripps Research Institute
La Jolla
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Nievergelt, Caroline M; Wineinger, Nathan E; Libiger, Ondrej et al. (2014) Chip-based direct genotyping of coding variants in genome wide association studies: utility, issues and prospects. Gene 540:104-9
Scott-Van Zeeland, A A; Bloss, C S; Tewhey, R et al. (2014) Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 19:724-32
Head, Steven R; Komori, H Kiyomi; LaMere, Sarah A et al. (2014) Library construction for next-generation sequencing: overviews and challenges. Biotechniques 56:61-4, 66, 68, passim
Park, Sung Kyu Robin; Aslanian, Aaron; McClatchy, Daniel B et al. (2014) Census 2: isobaric labeling data analysis. Bioinformatics 30:2208-9
Norden-Krichmar, Trina M; Gizer, Ian R; Libiger, Ondrej et al. (2014) Correlation analysis of genetic admixture and social identification with body mass index in a Native American community. Am J Hum Biol 26:347-60
Magdeldin, Sameh; Yamamoto, Keiko; Yoshida, Yutaka et al. (2014) Deep proteome mapping of mouse kidney based on OFFGel prefractionation reveals remarkable protein post- translational modifications. J Proteome Res 13:1636-46
Levitsky, Josh; Mathew, James M; Abecassis, Michael et al. (2013) Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology 57:239-48
Bendjilali, Nasrine; Kim, Helen; Weinsheimer, Shantel et al. (2013) A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation. PLoS One 8:e71434
Head, Steven R; Mondala, Tony; Gelbart, Terri et al. (2013) RNA purification and expression analysis using microarrays and RNA deep sequencing. Methods Mol Biol 1034:385-403
LaMere, Sarah A; Komori, H Kiyomi; Salomon, Daniel R (2013) New opportunities for organ transplantation research: epigenetics is likely to be an important determinant of the host immune response. Epigenomics 5:243-6

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