Background. Both over-immunosuppression and under-immunosuppression can endanger the health of a kidney transplant recipient (KTR). Genotyping KTRs to personalize the administration of immunosuppressive drugs, such as FK506, could help to reduce the incidence of complications like acute cellular rejection and BK viremia (BKV).
Objective. To determine if there are any associations between clinical outcomes involving over- and under-immunosuppression of KTRs receiving FK506 and selected polymorphisms in two genes: the pregnane X receptor gene NR1I2 (which promotes xenobiotic clearance) and two subunits of calcineurin (the target of FK506).
Methods. We determined genotypic and allelic frequencies of 87 adult KTRs for polymorphisms in NR1I2 (rs2275707), PPP3CA (rs3804410 and rs3804358), and PPP3CB (rs3763679). We used Pearsons chi-square and Fishers Exact Tests to analyze any associations between the SNPs and incidence of BKV or biopsy-proven acute rejections within the first year, and eGFR, FK506 weight-adjusted dosage, or dose-adjusted exposure to FK506 at month one.
Results. A genotypic association was found between polymorphisms in PPP3CA (rs3804410) and the weight-adjusted daily dose of FK506 at month one (p=0.0201). A genotypic and allelic association was found between polymorphisms in PPP3CB (rs3763679) and incidence of BKV within the first year after transplant (p=0.0034, 0.011). No other associations were found in any other combinations of SNPs and clinical outcomes.
|Gene||rs Number||Genotype/Allele||Low Dose, n (%)||High Dose, n (%)||p-value|
|PPP3CA||rs3804410||CC||8 (20)||13 (31)||0.020|
|CT||27 (66)||15 (36)|
|TT||6 (15)||14 (33)|
|C allele||43 (52)||41 (49)||0.7518|
|T allele||39 (48)||43 (51)|
|Gene||rs Number||Genotype/Allele||No BKV, n (%)||BKV, n (%)||p-value|
|PPP3CB||rs3763679||CC||41 (82)||12 (48)||0.0034|
|CT||9 (18)||13 (52)|
|TT||0 (0)||0 (0)|
|C allele||91 (91)||37 (74)||0.011|
|T allele||9 (9)||13 (26)|
Conclusion. The associations between the PPP3CB T allele and CT genotype with BKV suggest that these KTRs may be more susceptible to clinically significant over-immunosuppression. This is compatible with other studies suggesting that the T allele is associated with lower gene functionality. There is also a statistically significant unadjusted association between the PPP3CA CT genotype and low weight-adjusted FK506 dosing.
To cite this abstract in AMA style:Horwath M, Reignier T, Stone R, Yap M, Shah T, Naraghi R, Hutchinson I. Calcineurin Polymorphisms Associate with FK506 Dosage and Incidence of BK Viremia in Kidney Transplant Recipients [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/calcineurin-polymorphisms-associate-with-fk506-dosage-and-incidence-of-bk-viremia-in-kidney-transplant-recipients/. Accessed September 18, 2021.
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