Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type�2 diabetes mellitus in Pima Indians

Abstract

Recent studies have suggested that prostaglandin-endoperoxide synthase-2 (PTGS2), also known as cyclo-oxygenase 2, plays an etiological role in the development of type 2 diabetes mellitus (T2DM). PTGS2 generates prostaglandins, which negatively modulate glucose-stimulated insulin secretion, and functions as a mediator of the inflammatory response, which is associated with decreased insulin sensitivity. Moreover, the gene encoding this enzyme, PTGS2, is located on 1q25.2, a region that has been linked with early onset T2DM in Pima Indians. To determine the possible role played by PTGS2 in modulating susceptibility to T2DM, we screened approximately 7.0 kb of the gene, corresponding to the promoter, coding sequence, and flanking exon-intron boundaries, and identified five variants, including three single nucleotide polymorphisms (SNPs) in the promoter, one intronic SNP, and one in the 3' untranslated region. With the exception of one rare promoter SNP (minor allele frequency <0.03), all SNPs were typed in approximately 1000 Pima Indians. The range of frequencies for the more common alleles was 0.65-0.88, and we found substantial linkage disequilibrium between all PTGS2 SNP pairs (D'>/=0.95). Variant alleles at two markers, rs20417 and rs2066826, which are located in the promoter and intron 6, respectively, were in strong linkage disequilibrium with each other (D'=0.97) and were associated with a higher prevalence of T2DM. For marker rs20417, individuals with the variant CC genotype had a 30% higher T2DM prevalence compared with subjects with the GG genotype (odds ratio=1.6 per copy of C allele; P=0.01). The variant C allele of rs20417 has been associated with decreased PTGS2 promoter activity, thereby suggesting a possible biological consequence attributable to this polymorphism. These findings indicate that genetic variants in PTGS2 may play a role in mediating susceptibility to T2DM in Pima Indians and are consistent with the hypothesis that chronic inflammation may contribute to the development of T2DM in some individuals.

Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma

“…In our study, analysis of four haplotype-tagging SNPs in the regulatory regions scattered over the entire Cox-2 gene revealed important aspects of its allelic structure with consequences for adenoma risk and interactions with NSAIDs. Cox-2 is an inducible enzyme and its expression and stability appear to be subjected to very complex mechanisms regulated by various elements in both the 5 0 UTR and 3 0 UTR of the transcript as well as intronic sequences (Dixon et al, 2000;Kirtikara et al, 2000;Finkbeiner, 2001;Tanabe and Tohnai, 2002;Konheim and Wolford, 2003). Several promoter elements, such as CRE as well as those specific for binding to a variety of nuclear regulatory factors including NfkB, NF-IL6, and myb, may play an important regulatory role in the transcription of the Cox-2 gene in a tissuespecific manner (Potter et al, 2000;Mestre et al, 2001;Tang et al, 2001).…”

“…A common promoter variant, À765 G/C (rs20417/ ss5112606), which is located in the putative Sp1 binding site, was reported to have reduced promoter activity and was associated with reduced plasma C-reactive protein levels with implications for various inflammatory responses (Papafili et al, 2002) and with a decreased risk for myocardial infarction and stroke (Cipollone et al, 2004). Pima Indians with the variant homozygote genotype at this promoter polymorphism (reported as À899 G/C, rs20417/ ss5112606) were found to have a 30% higher prevalence of type II diabetes mellitus (Konheim and Wolford, 2003). Recently, allelic variations in the Cox-2 gene have been analysed for their association with cancer development.…”

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

“…Numerous COX-1 and COX-2 single nucleotide polymorphisms (SNPs) have been identified, and a more complete discussion of them has been done by Ulrich et al (2002) and Cipollone and Patrono (2002). Silent and nonsilent SNPs have been identified in COX coding regions, and SNPs of unknown function have also been identified in COX introns, untranslated regions, and upstream regulatory regions (Fritsche et al, 2001;Cipollone and Patrono, 2002;Ulrich et al, 2002;Halushka et al, 2003;Konheim and Wolford, 2003).…”

The -765G>C Cyclooxygenase-2 Promoter Polymorphism is associated with Type 2 Diabetes Mellitus, Low High-density Lipoprotein and Manifest Angina

“…The G allele is associated with more efficient binding of Sp1 and NF-κB transcription factors, increasing transcription of COX-2 [16]. The CC genotype has been shown to be associated with increased Type 2 diabetes mellitus prevalence of risk [17].…”