No abstract

IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohn's disease suggesting possible common underlying pathogenesis.

By screening the 1470 bp 5′ to the start codon of the human β2 adrenergic receptor gene, we have identified a total of eight polymorphisms (−20 T→C, −47 T→C, −367 T→C, −468 C→G, −654 G→A, −1023 G→A, −1343 A→G and −1429 T→A c.f. β2 adrenergic receptor start codon). Transient transfection of 5′ flanking deletion luciferase reporter constructs demonstrated the majority of activity of the human β2 adrenergic gene 5′ flanking region to be present within a 549 bp fragment immediately upstream from the start codon. Because of linkage disequilibrium, some combinations of polymorphisms were particularly frequent. We transiently transfected COS‐7 cells with luciferase constructs under the control of the 549 bp of 5′ flanking DNA containing the two most frequent extended haplotypes in this region. Luciferase activity was significantly reduced in cells transfected with the ‘mutant’ construct (−20C, −47C, −367C, −468G) c.f. the ‘wild‐type’ construct (−20T, −47T, −367T, −468C). These data suggest that polymorphisms have the potential to alter human β2 adrenergic receptor gene expression.British Journal of Pharmacology (1999) 126, 841–844; doi:10.1038/sj.bjp.0702385

Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGFβ1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17-19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD.