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Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients

Validation of rs2910164 in MicroRNA MIR146A

Oetting, William S. PhD1; Schladt, David P. MS2; Dorr, Casey R. PhD2,3; Wu, Baolin PhD4; Guan, Weihua PhD4; Remmel, Rory P. PhD5; Iklé, David PhD6; Mannon, Roslyn B. MD7; Matas, Arthur J. MD8; Israni, Ajay K. MD, MS3,4,9; Jacobson, Pamala A. PharmD1 for the DeKAF Genomics and GEN03 Investigators

doi: 10.1097/TP.0000000000002659
Original Basic Science—General
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Background. Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism.

Methods. In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans.

Results. Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4.

Conclusions. Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients.

1 Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN.

2 Hennepin Healthcare Research Institute, Minneapolis, MN.

3 Department of Medicine, Hennepin Healthcare, Minneapolis, MN.

4 Department of Biostatistics, University of Minnesota, Minneapolis, MN.

5 Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN.

6 Rho, Chapel Hill, NC.

7 Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL.

8 Department of Surgery, University of Minnesota, Minneapolis, MN.

9 Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN.

Received 28 August 2018. Revision received 16 November 2018.

Accepted 8 December 2018.

The authors declare no conflicts of interest.

Clinical Trial Notation: NCT00270712 and NCT01714440.

W.S.O., D.P.S., B.W., W.G, A.K.I., and P.A.J. participated in research design, writing of the article, performance of the research, and in data analysis. C.R.D. participated in the writing of the paper, the performance of the research, and in data analysis. R.P.R., R.B.M., and A.J.M. participated in research design, the performance of the research, and in the writing of the article. D.I. participated in research design and in the performance of the research.

W.S.O., D.P.S., B.W., W.G., D.I., and P.A.J. were supported by the National Institutes of Health NIAID Genomics of Transplantation (5U19-AI070119). A.J.M. was supported by the National Institutes of Health Genomics of Transplantation (5U19-AI070119), ARRA supplement (5U19-AI070119), and DeKAF (5U01-AI058013). A.K.I. was supported by the National Institutes of Health Genomics of Transplantation (5U19-AI070119) and ARRA supplement (5U19-AI070119).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: William S. Oetting, PhD, Department of Experimental and Clinical Pharmacology, University of Minnesota, 7–115 Weaver-Densford Hall, 308 Harvard St SE, Minneapolis, MN 55455. (oetti001@umn.edu).

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