title: Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes.
abstract: Extrarenal adverse effects (AEs) associated with calcineurin inhibitor (CNI) and mycophenolic acid (MPA) occur frequently but are unpredictable posttransplant complications. AEs may result from intracellular CNI accumulation and low activity of P-glycoprotein, encoded by the ABCB1 gene. Since ABCB1 single nucleotide polymorphisms (SNPs) and sex influence P-glycoprotein, we investigated haplotypes and extrarenal AEs. A prospective, cross-sectional study evaluated 149 patients receiving tacrolimus and enteric coated mycophenolate sodium or cyclosporine and mycophenolate mofetil. Immunosuppressive AE assessment determined individual and composite gastrointestinal, neurologic, aesthetic, and cumulative AEs. Lipids were quantitated after 12-hour fast. ABCB1 SNPs: c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) were determined with haplotype associations computed using the THESIAS program, and evaluated by immunosuppression, sex and race using multivariate general linear models. Tacrolimus patients exhibited more frequent and higher gastrointestinal AE scores compared with cyclosporine with association to CTT (P = 0.018) and sex (P = 0.01). Aesthetic AE score was 3 times greater for cyclosporine with TTC haplotype (P = 0.005). Females had higher gastrointestinal (P = 0.022), aesthetic (P < 0.001), neurologic (P = 0.022), and cumulative AE ratios (P < 0.001). Total cholesterol (TCHOL), low-density lipoproteins (LDL), and triglycerides were higher with cyclosporine. The TTC haplotype had higher TCHOL (P < 0.001) and LDL (P = 0.005). Higher triglyceride (P = 0.034) and lower high-density lipoproteins (P = 0.057) were associated with TTT with sex-adjusted analysis. ABCB1 haplotypes and sex were associated with extrarenal AEs. Using haplotypes, certain female patients manifested more AEs regardless of CNI. Haplotype testing may identify patients with greater susceptibility to AEs and facilitate CNI individualization.
authors.affiliation: From the Nephrology Division; Medicine, School of Medicine and Biomedical Sciences (RCV, SC, NL, AG, NN, KMT); Erie County Medical Center, Buffalo, New York (RCV, AG, KMT); Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences (CJM, SEM, LMC, KMT); Pharmacy, School of Pharmacy and Pharmaceutical Sciences (CJM, SEM, KMT); Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York (JDC, GEW); and Department of Pharmaceutical Sciences, College of Pharmacy, University of New England, Portland, Maine (DB).
authors.forename: Rocco C
authors.initials: RC
authors.lastname: Venuto
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Meaney
authors.forename: Shirley
authors.initials: S
authors.lastname: Chang
authors.forename: Nicolae
authors.initials: N
authors.lastname: Leca
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Consiglio
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Wilding
authors.forename: Daniel
authors.initials: D
authors.lastname: Brazeau
authors.forename: Aijaz
authors.initials: A
authors.lastname: Gundroo
authors.forename: Neha
authors.initials: N
authors.lastname: Nainani
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Morse
authors.forename: Louise M
authors.initials: LM
authors.lastname: Cooper
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Tornatore
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D065095:Calcineurin Inhibitors / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012737:Sex Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D065095:Calcineurin Inhibitors; D009173:Mycophenolic Acid