Repositorio
Institucional

Crespo Hirata, Rosario Dominguez

Brayan Campos-Salazar, Antony

Genvigir, Fabiana Dalla Vecchia

Felipe, Claudia Rosso

Tedesco-Silva, Helio

Medina-Pestana, Jose

Monteiro, Gabriela Vieira

Basso, Rodrigo de Gouveia

Cerda, Alvaro

Hirata, Mario Hiroyuki

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients

FRONTIERS MEDIA SA

FRONTIERS IN PHARMACOLOGY

en

Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated in Brazilian kidney transplant recipients within the 1-year post-transplant. Two-hundred and sixty-nine kidney transplant recipients were enrolled at a kidney transplant center in Sao Paulo city, Brazil, and treated with tacrolimus plus everolimus or mycophenolate sodium (clinical trial NCT01354301). Clinical and laboratory data, including renal function parameters and drug blood levels were recorded. Genomic DNA was extracted from blood samples. Polymorphisms in MTOR rs1057079 (c.4731G>A), rs1135172 (c.1437T>C), and rs1064261 (c.2997C>T), PPP3CA rs3730251 (c.249G>A), FKBP1A rs6033557 (n.259+24936T>C), FKBP2 rs2159370 (c.-2110G>T), and FOXP3 rs3761548 (c.-23+2882A>C) and rs2232365 (c.-22-902A>G) were analyzed by real-time PCR. Frequencies of gene polymorphisms did not differ among the treatment groups. Analysis of primary outcomes showed that patients carrying MTOR c.1437CC and FOXP3 c.-23+2882CC genotypes had higher serum creatinine than non-carriers (p < 0.05) at 1-year post-transplant. MTOR c.4731G allele (AG+GG genotype) was associated with increased risk for acute rejection (OR = 3.53, 95% CI = 1.09-11.48, p = 0.037). Moreover, 1-year cumulative incidence of rejection was higher in MTOR c.4731G allele carriers compared to AA genotype carriers (p = 0.027). Individually, analysis of secondary outcomes revealed that FKBP2 c.-2110GG genotype carriers had higher risk of leukopenia, FKBP1A n.259+24936C allele carriers had increased risk of constipation, and FOXP3 c.-22-902A or c.-23+2882A allele had higher risk of gastrointestinal disorders (p < 0.05). However, these results were not maintained in the multivariable analysis after p-value adjustment. In conclusion, variants in genes of mTOR and calcineurin pathways are associated with long-term impaired renal function, increased risk of acute rejection, and, individually, with adverse events in Brazilian kidney transplant recipients.

El monitoreo de fármacos inmunosupresores, como la calcineurina y los inhibidores de mTOR, es esencial para evitar resultados indeseables del trasplante renal. Los polimorfismos en genes relacionados con la farmacocinética se han asociado con la variabilidad en los niveles sanguíneos de fármacos inmunosupresores y efectos adversos, pero la influencia de los genes relacionados con la farmacodinámica aún está por dilucidar. La influencia de los polimorfismos en genes de las vías de señalización de mTOR y calcineurina en los resultados clínicos a largo plazo se investigó en receptores brasileños de trasplante renal dentro del año posterior al trasplante. Doscientos sesenta y nueve receptores de trasplante renal se inscribieron en un centro de trasplante renal en la ciudad de São Paulo, Brasil, y fueron tratados con tacrolimus más everolimus o micofenolato de sodio (ensayo clínico NCT01354301). Se registraron datos clínicos y de laboratorio, incluyendo parámetros de función renal y niveles sanguíneos del fármaco. El ADN genómico se extrajo de muestras de sangre. Se analizaron los polimorfismos en MTOR rs1057079 (c.4731G>A), rs1135172 (c.1437T>C) y rs1064261 (c.2997C>T), PPP3CA rs3730251 (c.249G>A), FKBP1A rs6033557 (n.259+24936T>C), FKBP2 rs2159370 (c.-2110G>T) y FOXP3 rs3761548 (c.-23+2882A>C) y rs2232365 (c.-22-902A>G) mediante PCR en tiempo real. La frecuencia de los polimorfismos génicos no difirió entre los grupos de tratamiento. El análisis de los resultados primarios mostró que los pacientes portadores de los genotipos MTOR c.1437CC y FOXP3 c.-23+2882CC presentaron niveles de creatinina sérica más altos que los no portadores (p < 0,05) al año del trasplante. El alelo MTOR c.4731G (genotipo AG+GG) se asoció con un mayor riesgo de rechazo agudo (OR = 3,53

IC del 95 % = 1,09-11,48

p = 0,037). Además, la incidencia acumulada de rechazo al año fue mayor en los portadores del alelo MTOR c.4731G que en los portadores del genotipo AA (p = 0,027). Individualmente, el análisis de los resultados secundarios reveló que los portadores del genotipo FKBP2 c.-2110GG presentaron un mayor riesgo de leucopenia, los portadores del alelo FKBP1A n.259+24936C presentaron un mayor riesgo de estreñimiento, y los portadores del alelo FOXP3 c.-22-902A o c.-23+2882A presentaron un mayor riesgo de trastornos gastrointestinales (p < 0,05). Sin embargo, estos resultados no se mantuvieron en el análisis multivariable tras el ajuste del valor p. En conclusión, las variantes en los genes de las vías mTOR y de la calcineurina se asocian con deterioro de la función renal a largo plazo, mayor riesgo de rechazo agudo y, individualmente, con eventos adversos en receptores brasileños de trasplante renal.

Artículo original

Este trabajo contó con el apoyo de becas del CNPq (n.° 306061/2013-9) y la FAPESP (2016/13118-8), Brasil. AC-S, GM y RB recibieron becas del CNPq y la USP, Brasil. MH, RH y FG también recibieron becas del CNPq y la FAPESP, Brasil.

This work was supported by grants from CNPq (

306061/2013-9) and FAPESP (2016/13118-8), Brazil. AC-S, GM, and RB had fellowships from CNPq and USP, Brazil. MH, RH, and FG are recipients of fellowships from CNPq and FAPESP, Brazil.

10.3389/fphar.2018.01296

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kidney transplant

immunosuppressive drugs

mTOR

calcineurin

FOXP3

pharmacogenetics

trasplante de riñón

medicamentos inmunosupresores

mTOR

calcineurina

FOXP3

farmacogenética

Pharmacology & Pharmacy

kidney transplant

immunosuppressive drugs

mTOR

calcineurin

FOXP3

pharmacogenetics

trasplante de riñón

medicamentos inmunosupresores

mTOR

calcineurina

FOXP3

farmacogenética

Farmacología y Farmacia

Genética Humana

Transplantes

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acceso abierto

acceso abierto

WOS:000450092900001

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients

Artículo original

FRONTIERS MEDIA SA

FRONTIERS IN PHARMACOLOGY

Farmacología y farmacia

1663-9812

en

CNPq 306061/2013-9

FAPESP 2016/13118-8

USP

This work was supported by grants from CNPq (# 306061/2013-9) and FAPESP (2016/13118-8), Brazil. AC-S, GM, and RB had fellowships from CNPq and USP, Brazil. MH, RH, and FG are recipients of fellowships from CNPq and FAPESP, Brazil.

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CNPq 306061/2013-9#FAPESP 2016/13118-8#USP