Gene Variants and Haplotypes Modifying Transcription Factor Binding Sites in the Human Cyclooxygenase 1 and 2 (PTGS1 and PTGS2) Genes

Abstract

Cyclooxygenases (prostaglandin-endoperoxide synthases, (EC 1.14.99.1) 1 and 2 (COX-1 and COX-2)) are key enzymes with a highly functional and pharmacological relevance. Genetic variations in the corresponding genes PTGS1 and PTGS2 are related to diverse human disorders and adverse drug reactions. Although COX-2 is highly inducible, most genetic association studies have focused on coding region gene variants. The aim of this study is to analyze the genetic variants modifying transcription factor binding sites in human PTGS genes based on the combined use of bioinformatics with 1,000 genomes data and replication by next generation sequencing. Updated information on gene sequences and variants was obtained from the 1,000 genomes website and from a replication sequencing study. Of the 570 upstream PTGS1 gene variants, 43 altered binding sites, either by disrupting existing sequences or by creating new binding sites. The most relevant are the SNP rs72769722, which creates a new binding site for NFKB, and the SNPs rs73559017 and rs76403914, both disrupting binding sites for CDX1. Of the 682 upstream PTGS2 gene variants, 31 altered binding sites, the most relevant being rs689466 and rs20417, which disrupt binding sequences for MYB and E2F, respectively; rs689462 which creates a new binding site for POU3F2; and a haplotype combining the SNPs rs34984585+rs10911904, which creates a new binding site for SRY. This study provides a detailed catalog of variant and invariant transcription factor binding sites for PTGS genes and related haplotypes. This information can be useful to identify potential genetic targets for studies related to COX enzymes.

The Genetics of Drug Hypersensitivity Reactions

“…Using this approach we investigated the 5' upstream regions of COX-1 and -2 and their influence on transcription factor binding and gene expression [136]. Other SNPs with functional effects can be found in these genes [137], and next-generation sequencing studies in patients with hypersensitivity to NSAIDs are ongoing.…”

Genetic polymorphisms in very important pharmacogenomic (VIP) variants in the Tibetan population

“…Previous studies have associated the rs689466 expression with many diseases, such as asthma (Shi et al, 2008;Ho and Chew, 2010), breast cancer (Dai et al, 2014), and pancreatic cancer (Zhao et al, 2009). The A variant of rs689466 (-1195 G>A) creates a v-Myb-binding site in the promoter that increases transcription (Zhang et al, 2005;Agundez et al, 2014), and is also significantly associated with increased risk of cancers of the digestive system, especially among the Asian populations (Dong et al, 2010). Asian individuals with the G allele have higher blood pressure (Iwai et al, 2004;Jin et al, 2008).…”

A case‐control study and meta‐analysis reveal the association between COX‐2 G‐765C polymorphism and primary end‐stage hip and knee osteoarthritis

“…In addition to growing evidence indicating that the COX‐2‐PGE2 axis is involved in the pathogenesis of OA, several genetic single nucleotide polymorphisms (SNPs) in COX‐2 have also shown an association with OA susceptibility . G‐765C (rs20417) is one of the most investigated polymorphisms due to its location in the promoter of COX‐2 , and it may affect COX‐2 expression by altering the transcription factor binding site . Additionally, the ‐765C allele possessed significantly lower promoter activity (30%) compared to the ‐765G allele .…”

“…9,18 G-765C (rs20417) is one of the most investigated polymorphisms due to its location in the promoter of COX-2, and it may affect COX-2 expression by altering the transcription factor binding site. 19 Additionally, the -765C allele possessed significantly lower promoter activity (30%) compared to the -765G allele. 20 The linkage between the COX-2 G-765C polymorphism and OA susceptibility has been studied in German and Turkish populations with conflicting results.…”