Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression □ S

ABSTRACT There are a considerable number of reports identifying and characterizing genetic variants within the CYP2C9 coding region. Much less is known about polymorphic promoter sequences that also might contribute to interindividual differences in CYP2C9 expression. To address this problem, approximately 10,000 base pairs of CYP2C9 upstream information were resequenced using 24 DNA samples from the Coriell Polymorphism Discovery Resource. Thirty-one single-nucleotide polymorphisms (SNPs) were identified; nine SNPs were novel, whereas 22 were reported previously. Using both sequencing and multiplex single-base extension, individual SNP frequencies were determined in 193 DNA samples obtained from unrelated, selfreported Hispanic Americans of Mexican descent, and they were compared with similar data obtained from a non-Latino white cohort. Significant interethnic differences were observed in several SNP frequencies, some of which seemed unique to the Hispanic population. Analysis using PHASE 2.1 inferred nine common (Ͼ1%) variant haplotypes, two of which included the g.3608CϾT (R144C) CYP2C9*2 and two the g.42614AϾC (I359L) CYP2C9*3 SNPs. Haplotype variants were introduced into a CYP2C9/luciferase reporter plasmid using site-directed mutagenesis, and the impact of the variants on promoter activity assessed by transient expression in HepG2 cells. Both constitutive and pregnane X receptor-mediated inducible activities were measured. Haplotypes 1B, 3A, and 3B each exhibited a 65% decrease in constitutive promoter activity relative to the reference haplotype. Haplotypes 1D and 3B exhibited a 50% decrease and a 40% increase in induced promoter activity, respectively. These data suggest that genetic variation within CYP2C9 regulatory sequences is likely to contribute to differences in CYP2C9 phenotype both within and among different populations

Neonatal hyperbilirubinemia: Assessing variation in knowledge and practice.

IntroductionNeonatal hyperbilirubinemia (NH) is commonly diagnosed and managed by pediatricians in various clinical settings. The 2004 American Academy of Pediatrics (AAP) Clinical Practice Guideline on NH is widely cited, but literature examining variation across pediatric specialties is limited. This study aimed to assess baseline knowledge and practice habits regarding NH among pediatric providers across various specialties immediately prior to the release of the 2022 NH clinical practice guideline.MethodsA non-probability, convenience, self-selected sampling survey was electronically distributed to 311 subjects across five specialties within one pediatric healthcare institution. The survey included eight multiple choice knowledge-based questions with confidence assessments and five management-based questions assessing respondent agreement on a 5-point scale. To compare groups, the Kruskal-Wallis and Mann-Whitney tests were used for continuous variables, and the chi-square and Fisher's exact tests were used for categorical variables.ResultsThe overall survey response rate is 46%. There were significant differences between specialties' knowledge regarding NH (pConclusionsSignificant variations in knowledge and management of NH were identified among pediatric specialties. This suggests dissemination of new guidelines must be cognizant of different constraints impacting knowledge and practice across specialties