title: Inosine 5'-monophosphate dehydrogenase 1 haplotypes and association with mycophenolate mofetil gastrointestinal intolerance in pediatric heart transplant patients.
abstract: MMF, the most commonly used adjuvant immunosuppressant in pediatric heart transplantation, has frequent GI adverse events. SNPs in inosine 5'-monophosphate dehydrogenase I (IMPDH1) may contribute to MMF GI intolerance. Phased haplotypes may have more utility than individual SNPs in candidate gene association studies for complex traits. This study defined common IMPDH1 haplotypes and investigated whether these haplotypes influence MMF GI intolerance in 59 pediatric heart recipients. Genotypes were assessed by Taqman analysis of IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294, and rs2228075, and haplotypes were inferred using Arlequin 3.01 software. GI intolerance was defined as diarrhea, vomiting, nausea, or abdominal pain requiring MMF dose holding for > 48 h or MMF discontinuation. GI intolerance occurred in 21 patients (35.6%). Ten IMPDH1 haplotypes were identified in this population. In univariable analyses, one haplotype was strongly associated with MMF GI intolerance with 59.1% of carriers of this haplotype experiencing MMF GI intolerance compared to 21.6% of non-carriers (p = 0.005). In this study, we identify a common IMPDH1 haplotype associated with MMF GI intolerance in a population of pediatric heart transplant patients. This haplotype of interest did not demonstrate stronger association with MMF GI intolerance than an individual IMPDH1 SNP.
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Ohmann
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Vera
authors.initials: V
authors.lastname: Pravica
authors.forename: Maria M
authors.initials: MM
authors.lastname: Brooks
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Steven A
authors.initials: SA
authors.lastname: Webber
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006239:Haplotypes; D016027:Heart Transplantation / Q000379:methods*; D006579:Heterozygote; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010372:Pediatrics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors
chemical_list: D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D009173:Mycophenolic Acid